Open Access

Molecular targets and signaling pathways regulated by interleukin (IL)-24 in mediating its antitumor activities

Journal of Molecular Signaling20138:15

https://doi.org/10.1186/1750-2187-8-15

Received: 15 November 2013

Accepted: 21 December 2013

Published: 30 December 2013

Abstract

Cancer remains a major health issue in the world and the effectiveness of current therapies is limited resulting in disease recurrence and resistance to therapy. Therefore to overcome disease recurrence and have improved treatment efficacy there is a continued effort to develop and test new anticancer drugs that are natural or synthetic - (conventional chemotherapeutics, small molecule inhibitors) and biologic (antibody, tumor suppressor genes, oligonucleotide) product. In parallel, efforts for identifying molecular targets and signaling pathways to which cancer cells are “addicted” are underway. By inhibiting critical signaling pathways that is crucial for cancer cell survival, it is expected that the cancer cells will undergo a withdrawal symptom akin to “de-addiction” resulting in cell death. Thus, the key for having an improved and greater control on tumor growth and metastasis is to develop a therapeutic that is able to kill tumor cells efficiently by modulating critical signaling pathways on which cancer cells rely for their survival.

Currently several small molecule inhibitors targeted towards unique molecular signaling pathways have been developed and tested in the clinic. Few of these inhibitors have shown efficacy while others have failed. Thus, targeting a single molecule or pathway may be insufficient to completely block cancer cell proliferation and survival. It is therefore important to identify and test an anticancer drug that can inhibit multiple signaling pathways in a cancer cell, control growth of both primary and metastatic tumors and is safe.

One biologic agent that has the characteristics of serving as a potent anticancer drug is interleukin (IL)-24. IL-24 suppresses multiple signaling pathways in a broad-spectrum of human cancer cells leading to tumor cell death, inhibition of tumor angiogenesis and metastasis. Additionally, combining IL-24 with other therapies demonstrated additive to synergistic antitumor activity. Clinical testing of IL-24 as a gene-based therapeutic for the treatment of solid tumors demonstrated that IL-24 is efficacious and is safe. The unique features of IL-24 support its further development as an anticancer drug for cancer treatment.

In this review we summarize the current understanding on the molecular targets and signaling pathways regulated by IL-24 in mediating its anticancer activity.

Keywords

IL-24 Tumor suppressor Cytokine IL-10 Cancer Apoptosis Autophagy Cancer stem cells Clinical trial

Review

Interleukin (IL)-24

The IL-24 gene originally referred to melanoma differentiation associated gene -7 (mda-7) belongs to the IL-10 cytokine superfamily. IL-24 DNA sequence includes an IL-10 signature and is composed of 7 exons and 6 introns and is located in a small 195 kb gene cluster on chromosome 1q31-32 [1, 2]. Interestingly, several members of the IL-10 family of cytokines including IL-10, IL-19 and IL-20 are located on chromosome 1q31-32 [1, 2]. Additional members of the IL-10 cytokine family located on different chromosome include IL-22, IL-26, IL-28A and IL-28B [3]. In this review we will refer mda-7 as IL-24 for consistency and interchange of IL-24 for mda-7 at any section of the review refers to the same gene and protein.

The IL-24 gene was originally discovered by subtraction hybridization method by exposing human melanoma cells (HO1 cell line) to the terminal differentiation inducing agents such as IFN-beta (IFN-β) and mezerin [4, 5]. The cDNA of IL-24 is 1718-bp in length and encodes an evolutionarily conserved protein of 206 amino acids with a predicted molecular weight of 23.8 KD [5]. The 3′-untranslated region (UTR) of IL-24 mRNA has three consensus elements (AUUUA) and three polyadenylation signals (AAUAAA) which is involved in mRNA stability and regulation respectively [1, 6]. Sequence analysis of IL-24 showed that it has an N-terminal hydrophobic signal peptide of 49 amino-acid in length that allows the IL-24 protein to be cleaved and secreted [7]. IL-24 has five phosphorylation (Serine 88, 101 & 161 and Threonine-111 &133) and three glycosylation sites (Cysteine 95, 109 and 126) [8, 9]. Additionally, IL-24 protein has been shown to undergo ubiquitination and proteasome-mediated degradation [10]. IL-24 protein phosphorylation, glycosylation and ubiquitination suggest that the protein undergoes post-translational modification (PTM).

The IL-24 coding region has less than 19% amino acid homology with human IL-10 while the homology with other IL-10 family members varies between 15-40% [11, 12]. The rat orthologue of human IL-24 is c49a/mob-5 which encodes a protein of 183 amino acids with a predicted molecular weight of 21.1-23 KD and has 63% homology with IL-24 [1316]. FISP is the mouse orthologue of IL-24 and encodes a protein of 220 amino acids with the predicted mass of 25 KD and has 69% identity to human IL-24 at the protein level [17]. Although C49A/MOB-5 and FISP have significant homology with IL-24 protein, the biological function of these proteins is different from human IL-24. Among the several members of the IL-10 cytokine family, IL-24 is the only member that exhibits direct antitumor activity both in vitro and in vivo, the details of which will be discussed in the sections described below.
  1. i)

    Clinical correlation suggesting IL-24 is a tumor suppressor. Clinical studies supporting IL-24 is a tumor suppressor or functions as a tumor suppressor was reported by two independent studies [18, 19]. Immunohistochemical analysis of melanocytes, nevi and in different stages of melanoma showed IL-24 protein expression progressively decreased with disease progression from primary to metastatic phase with complete loss of expression in the metastatic phase [18, 20]. Analysis of IL-24 expression in lung cancer showed an inverse correlation between IL-24 protein expression and disease progression [19]. Both of these studies showed loss of IL-24 protein expression correlated with disease progression and concluded IL-24 likely functions as a tumor suppressor. The studies also indicated that restoration of IL-24 protein expression might slow or suppress the disease.

     
  2. ii)

    Early preclinical study demonstrating IL-24 is a potential tumor suppressor. The first preclinical report showing IL-24 is a tumor suppressor gene was demonstrated by Jiang et al. [6]. Molecular studies revealed both mRNA and protein for IL-24 was detectable in normal melanocytes. However, in melanoma tissues IL-24 mRNA but not the protein was detectable suggesting loss of IL-24 protein expression occurred during cellular transformation. Although the preclinical study preceded the clinical studies, the findings were in complete agreement with the clinical observation.

    Follow-up studies showed that reintroducing exogenous IL-24 gene and restoring protein expression suppressed tumor growth both in vitro and in vivo[21]. Additionally, overexpression of IL-24 protein in normal cells did not elicit any cytotoxicity indicating IL-24 had selectivity towards tumor cells. These initial studies demonstrating IL-24 is a novel tumor suppressor/cytokine gene provided the impetus for conducting large scale studies testing IL-24 as an anticancer drug and unraveling the molecular mechanisms by which IL-24 exerted its antitumor activities.

     
  3. iii)

    IL-24 receptors. Studies from two independent laboratories reported the identification of two receptors for IL-24 called IL-20 receptor (IL-20R) and IL-22 receptor (IL-22R) [15, 22]. Both IL-20R and IL-22R exist as a heterodimer and is comprised of two subunits. IL-20R is comprised of IL-20R1 and R2 subunits while IL-22R is comprised of IL-22R1 and IL-20R2 subunits. Thus, IL-20R2 subunit is common and shared between IL-20 and IL-22 receptors. Within the IL-10 cytokine family, IL-19 can also bind to IL-20R while IL-20 can bind to both IL-20R and IL-22R [16, 23]. Although there is substantial sharing of receptors among the members of the IL-10 cytokine family, the biological activities of IL-24, IL-19 and IL-20 are quite distinct with only IL-24 exhibiting receptor-mediated antitumor activity in human cancer cells. Thus, the ligand-receptor interaction is complex and reveals the existence of underlying differences in intracellular signaling upon ligand binding to the receptor. However, studies are yet to unravel the intracellular signaling triggered by IL-24 directing tumor cells to undergo cell death versus those mediated by IL-19 and IL-20 that do not trigger tumor cell death. In addition, distribution and expression of these receptor complexes in various tumor tissues and normal tissues has not been thoroughly investigated and is warranted.

     

Studies conducted by Parrish-Novak et al. showed that IL-24 protein binds with equal affinity to the two receptor complexes [24]. The binding of IL-24 to its receptors resulted in the activation of the signal transducer and activation of transcription-3 (STAT-3) and to a lesser extent STAT-1 [25]. Lower concentration of IL-24 protein was shown to activate STAT-3 whereas very high concentration of IL-24 activated STAT-1 [26]. Since STAT-3 is known to signal for cell survival and proliferation, the importance of IL-24 mediated STAT-3 activation was tested using STAT-3 inhibitors in IL-24 receptor-positive tumor cells [26]. Knock-down of STAT-3 did not abrogate IL-24 protein-mediated cytotoxicity indicating STAT-3 was not required for IL-24-mediated antitumor activity. This study also demonstrated that IL-24 protein selectively kills receptor-positive but not receptor-negative tumor cells when bound to its receptor thus providing an extracellular-protein mediated tumor cell killing. No cytotoxicity was observed when IL-24 protein bound to receptor-positive normal cells.

IL-24-mediated antitumor activities involve regulation of multiple signaling pathways

a) Tumor cell killing

Since the initial report of IL-24 functioning as a tumor suppressor gene, studies from our laboratory and others have tested IL-24 as an anticancer drug for the treatment of a broad-spectrum of human cancers [11, 12, 2628]. The consensus from the large number of studies reported till date is that IL-24 functions as a tumor suppressor and IL-24-mediated cytotoxicity is selective towards tumor cells with minimal to no toxicity to normal cells. Another observation that is in agreement with all of the current reports is that the cellular signaling pathways that are regulated by IL-24 varies in different cancer cells tested and is cell-type dependent. However, all of the signaling pathways, irrespective of the cancer cell type, converge downstream on cellular apoptosis resulting in caspase activation and tumor cell death.

The various molecular signaling pathways that are regulated by IL-24 in human cancer cells leading to tumor cell killing is discussed below.

Apoptosis

Initial studies conducted in our laboratory showed adenovirus (Ad)-mediated IL-24 gene delivery in human lung cancer cells resulted in induction of tumor cell apoptosis also commonly referred to type-I programmed cell death (PCD) [29]. Molecular studies revealed Ad-IL24 activated the intrinsic apoptotic pathway as determined by the activation of cytochrome-C, caspase-9 and -3 [29]. Follow-up studies demonstrated IL-24 mediated tumor cell apoptosis was independent of the mutational status for p53, Ras, Bax and Rb [30]. Activation of c-Jun NH2-terminal kinase (JNK) by IL-24 and its requirement in IL-24-mediated apoptotic cell killing when combined with radiation was first demonstrated in human A549 lung cancer cells [30]. Follow-up studies in prostate cancer and glioma showed JNK activation when IL-24 treatment was combined with radiation [31, 32]. Subsequent to JNK activation, modulation of pro- (Bax and Bak) and anti-apoptotic (Bcl-Xl and Bcl-2) proteins were demonstrated in the prostate cancer model. Treatment with SP600125, a JNK inhibitor abrogated the tumor cell killing demonstrating JNK was required for IL-24-mediated tumor cell killing [32].

In melanoma cells, p38MAPK signaling was demonstrated to be important for IL-24-mediated tumor cell killing [33]. Activation of p38MAPK by IL-24 led to marked induction of DNA-damage-inducible (GADD) family of genes that included GADD153, GADD45α and GADD34 that culminated in apoptosis. A modest induction of GADD45γ was also noted in the study. Inhibiting p38MAPK with SB203580, a specific small molecule inhibitor abrogated IL-24-induced melanoma apoptosis [33]. Knock-down of GADD family of genes using antisense oligonucleotides also abolished IL-24- mediated cell death. Induction of GADD family of genes was also demonstrated in Ad-IL24-treated glioblastoma multiforme, prostate cancer, breast cancer and in pancreatic cancer cells that resulted in tumor cell apoptosis [34].

While reports of IL-24 functioning as a tumor suppressor and its ability to regulate apoptotic signaling pathways were exploding, Pataer et al. showed Ad-IL24 treatment of lung cancer cells resulted in activation of double stranded RNA-dependent protein kinase (PKR) protein resulting in tumor cell killing [35]. PKR belongs to the eukaryotic initiation factor (eIF) 2α kinase family. Additionally, in the same study they showed that activation of PKR by IL-24 resulted in the phosphorylation of eIF2α, TYK2, Stat1, Stat3 and p38MAPK proteins all of which are known to play a role in protein synthesis, growth suppression and induction of apoptosis. Follow-up studies by the same group investigated whether protein-protein interaction between IL-24 and PKR was important for tumor cell killing. Their study unveiled a new observation showing IL-24 physically bound the double stranded RNA-dependent protein kinase (PKR) protein and its binding resulted in phosphorylation of both proteins [36] that contributed to tumor cell killing. Additionally, requirement of PKR for IL-24-mediated cell killing was demonstrated using PKR wild-type (+/+) and PKR null (-/-) mouse embryo fibroblast (MEF) cells. Ad-IL24 exhibited cytotoxicity towards PKR+/+ but not to PKR -/- MEFs. These results established tumor suppressor activity of IL-24 required PKR. Follow-up studies in our laboratory tested the requirement of PKR in other cancer cell lines. Ad-IL24 treatment of prostate cancer cells showed PKR activation in LNCaP cells but not in DU145 cells [37]. In ovarian cancer cells, activation of Fas-Fas ligand pathway was shown to be more important in IL-24-mediated cell death than the PKR activation [38]. It is thus evident that the requirement of PKR in IL-24-mediated cell death is cell-type dependent and that IL-24 can exert its antitumor activity independent of PKR.

Another mechanism related to PKR is the activation of PKR like endoplasmic reticulum kinase (PERK) by IL-24 [39, 40]. PERK like PKR belongs to the eIF-2α family. Treatment of cells with Ad-IL24 resulted in IL-24 protein expression that bound and inactivated HSP70 family chaperone BiP/GRP78, which in turn promoted dissociation and activation of PKR-like endoplasmic reticulum kinase (PERK) resulting in initiation of tumor cell apoptosis. Involvement of PERK has also been demonstrated in IL-24-mediated apoptosis that involves induction of reactive oxygen species (ROS). Exogenous expression of IL-24 in tumor cells resulted in ROS production which in turn deregulated mitochondrial function via PERK dependent generation of lipid second messenger ceramide leading to cell death [12, 31, 41, 42]. Increase in intracellular ceramide levels facilitated calcium ion dependent generation of ROS production that amplified the autocrine signaling loop and effected tumor cells in both autocrine and paracrine fashion culminating in cell death.

Li et al. recently demonstrated IL-24 increases the level of ROS, followed by the induction of differentiation and programmed cell death, in SH-SY5Y neuroblastoma cells [43]. Subsequent studies conducted in prostate cancer cells showed treatment with antioxidants such as N-acetyl-L-cysteine and Tiron or with inhibitors of mitochondrial permeability transition (cyclosporine A and bongkrekic acid) abrogated Ad-IL24-induced apoptosis [44]. In contrast, treatment with agents that induce ROS production (arsenic trioxide, NSC656240 and PK11195) enhanced Ad-IL24 induced cellular apoptosis. Ad-IL-24 when combined with a ROS inducing agent demonstrated enhanced antitumor activity in a pancreatic mouse model and was independent of the K-ras status [45]. Ectopic expression of Bcl-2 and Bcl-XL inhibited Ad-IL24 induced mitochondrial changes, ROS production and apoptosis, which further substantiates the involvement of mitochondrial dysfunction in Ad-IL24 induced apoptosis [41]. In contrast to these findings, Lee et al. reported IL-24 inhibited hydrogen peroxide (H2O2) induced ROS production in normal vascular smooth muscle cells (VSMC) by reducing mitochondrial H2O2 production and by enhancing the expression of antioxidant enzymes [46]. It is evident from these reports that IL-24 selectively induces ROS-mediated cell death in tumor cells but not in normal cells.

Negative regulation of β-catenin and phosphatidylinositol 3-kinase (PI3K) pathways is another mechanism by which IL-24 exerts its anticancer activity in human breast, lung and pancreatic cancer cells [26, 47]. In continuation with these reports our laboratory has pursued to dissect the PI3K/Akt/mTOR pathway in human lung cancer cells that have been stably transfected to express exogenous IL-24. Preliminary results indicate IL-24 effectively inhibits Akt1/2 and its downstream target mTOR in lung cancer cells resulting in inhibition of cell growth, cell migration and invasion [48].

From the above reports it is evident that IL-24 induces tumor cell apoptosis by modulating various signaling pathways that is cell-type dependent.

Autophagy

Autophagy or type-II PCD occurs under physiological and pathological conditions in response to cellular stress such as nutrition deprivation, inflammation, hypoxia, and exposure to various drug treatments. Although autophagy was originally defined as a cell survival mechanism by which cells and cellular organelles are degraded and cleared without activating the host immune system. However, studies have demonstrated autophagy also plays an important role in cancer cell survival and death [49]. While there is fair amount of literature supporting cancer cells utilize the autophagy pathway for their survival, there also exists a significant number of reports demonstrating exposure of tumor cells to anti-cancer drugs results in autophagy-mediated tumor cell death [50]. Thus, autophagy plays a role in both cell survival and cell death and the switch from survival to death likely depends on the cellular stress threshold. On the basis of these observations, several laboratories are attempting to manipulate the autophagic process in cancer cells as a new method of cancer therapy.

Interests in studying whether IL-24 regulates autophagy in cancer cells arises from the initial observation and reports made by our laboratory and others [51, 52]. We and others showed enforced expression of IL-24 in tumor cells resulted in accumulation of IL-24 protein in the endoplasmic reticulum (ER) that lead to activation of the unfolded protein response (UPR) and expression of molecular chaperones such as glucose-regulated protein (GRP) 78/immunoglobulin binding protein (BiP) [53, 54]. Additionally, expression of PERK and activating transcription factor (ATF)-4 which are normally bound to and inactivated by BiP/GRP78 was shown to be regulated by IL-24. Activation of the UPR/GRP78/BiP pathway restores proper protein folding and thus reduces ER stress and prevents cells from undergoing cell death. However, accumulating data in the recent years suggests that autophagy is also initiated in response to ER stress caused by an overload of misfolded proteins [55].

Since IL-24 induced ER stress and regulated the UPR/GRP78/BiP pathway, the possibility of IL-24 inducing autophagy-mediated tumor cell death was investigated. Treatment of glioma cells with glutathione-S-transferase (GST)-IL24 fusion protein resulted in simultaneous activation of both autophagy and apoptosis [40]. Park et al. showed GST-IL24 protein-mediated autophagy in glioma cells was dependent on PERK-mediated ER stress that involved inactivation of ERK1/2 and activation of the JNK pathway [56, 57]. In the same study the authors showed GST-IL-24 induced PERK-dependent vacuolization of LC3-expressing endosomes formation in glioma cells that was suppressed when treated with inhibitors of autophagy. Finally, autophagy was shown to overlap with activation of the pro-apoptotic pathway culminating in tumor cell death. Yacoub et al. showed treatment of glioma cells with adenovirus (Ad)-IL24 induced ER stress and triggered intracellular ceramide production and ROS generation resulting in autophagic cell death [58]. Ad-IL24 when combined with OSU-03012, an autophagy inducing drug, enhanced the antitumor activity in glioma cells by increasing ER stress and simultaneously reducing anti-apoptotic (MCL-1 and BCL-XL) protein expression [59]. In renal cell carcinoma, IL-24 when combined with histone deacetylase inhibitors (HDACIs) elevated intracellular Ca2+ level and increased ROS production resulting in autophagy and cell death [60]. In prostate cancer cells but not in normal prostate epithelial cells, IL-24 induced autophagy through a canonical signaling pathway involving beclin-1, AuTophaGy-related (ATG)-5 and hVps34 [61]. Autophagy was observed to occur at earlier time points (< 24 h) that switched to apoptosis by 48 h after IL-24 treatment. Concurring with these findings, Yokoyama et al. showed human melanoma cells when treated with IL-24 protein induced beclin-1 resulting in autophagy at 24 h after treatment [62]. However, time course studies revealed switching from autophagy to apoptosis (unpublished data).

In contrast to the studies described above demonstrating IL-24 induced autophagy facilitated cell killing, Yang et al. using a conditionally replicating adenovirus (ZD55) reported exogenous expression of IL-24 in chronic lymphocytic leukemia B-cells induced autophagy via upregulation of beclin-1 that promoted cell survival [63]. However, when the cells were treated with wortmanin, an autophagy inhibitor, IL-24-mediated autophagosomes were inhibited resulting in killing of the leukemia cells.

It is evident from the above reports that IL-24-mediated cell killing involves both autophagy and apoptosis. The study results also suggest that combining IL-24 with activators of apoptosis and autophagy will produce enhanced antitumor activity and will be beneficial in cancer treatment. However, caution needs to be taken when IL-24-based combination therapy are planned and should be tailored based on the cancer type being studied. As evident from the leukemia study, inhibiting autophagy will be beneficial for producing enhanced antitumor activity with IL-24.

b) Bystander effect

Initial studies conducted in our laboratory and others focused on testing IL-24 as a cancer gene therapeutic using viral and non-viral vectors and investigating the molecular mechanism of cell killing. However, since IL-24 DNA sequence revealed a secretory signal sequence it was postulated that IL-24 protein is secreted. Studies from our laboratory and others have demonstrated IL-24 protein is glycosylated and secreted [2, 64]. The question that arose next was whether the secreted protein had any antitumor activity and if IL-24 receptors were required for the activity? Another question raised was whether the secreted IL-24 protein had any inhibitory effect on neighboring tumor cells that did not express IL-24? Finally, whether IL-24 exerted its antitumor activity by both intracellular and extracellular mechanism was to be resolved.

The answers to the questions were partly resolved by studies conducted in our laboratory and others. Treatment of human pancreatic tumor cells and melanoma cells with human IL-24 protein produced in eukaryotic cells exhibited potent cytotoxicity [11, 26]. The authors in these studies showed the cytotoxicity was selective towards receptor-positive tumor cells and spared receptor-positive normal cells. Additionally, it was demonstrated that IL-24 protein utilized its receptors for mediating the antitumor activity in tumor cells. Receptor-negative tumor cells did not undergo cell death when treated with IL-24 protein. Although ligand-receptor mediated cell killing was demonstrated, the receptor utilization by IL-24 protein varied among tumor types. For example in melanoma cell lines, IL-20 receptor was shown to be required while IL-22 receptor was required in pancreatic cancer cell lines. Thus, the usage of the receptors can vary among tumor cell lines [11, 26]. Molecular studies revealed IL-24 on binding to its receptors resulted in activation of signal transducer and activator of transcription (STAT)-3 and expression of the pro-apoptotic Bax protein resulting in apoptotic cell death [26]. However, knock-down of STAT-3 did not abrogate IL-24 protein-mediated killing of the receptor-positive tumor cells indicating STAT-3 activation was not required for tumor cell killing. Concurring with these findings was the report showing IL-24 protein produced in bacteria killed human breast and prostate cancer cells with no toxicity to normal cells [12]. The results from all of the studies revealed that glycosylation of IL-24 protein was not required for mediating its antitumor activity but was required for its stability in the extracellular environment.

Subsequent studies showed receptor-positive tumor cells transduced with Ad-IL-24 or transfected with IL-24 plasmid DNA and overexpressing IL-24 when mixed with receptor-negative tumor cells resulted in killing of both receptor-positive and –negative cells [29, 65]. This observation indicated IL-24 could exert a “bystander” tumor killing effect. Su et al. demonstrated normal cells infected with Ad.MDA-7 and co-cultured with cancer cells resulted in reduced cell viability [64]. When the normal and tumor cells were separated by agar overlay thereby eliminating any physical contact between the two cell types, tumor cell killing still occurred. These studies elegantly demonstrated that IL-24 protein could diffuse through agar, bind to receptor-positive tumor cells and reduce tumor cell viability, alter anchorage-independent growth, and radiosensitize culminating in apoptotic cell death.

In vivo studies demonstrated mice implanted with a mixture of IL-24 producing human embryonic kidney cells (HEK)-293 and human receptor-negative A549 lung tumor cells underwent tumor growth inhibition [66]. Molecular studies revealed IL-24 protein was secreted and circulating IL-24 protein was detectable in serum collected from mice. The antitumor activity was proven to occur by IL-24 protein affecting the IL-24 receptor-positive tumor endothelial cells and inhibiting tumor angiogenesis. Additionally, inhibition of contralateral tumors was demonstrated establishing the concept of IL-24 protein can suppress tumor growth by exerting a “bystander effect”.

In another study, intratumoral injection of Ad-IL24 into a flank tumor resulted in shrinkage of contralateral tumor [67]. In this study, human T47D breast carcinoma cells were implanted into both flanks of nude mice and Ad.MDA-7 was injected only in the left side of the tumor. Apart from having a significant reduction in the tumor growth treated with Ad.MDA-7, inhibition of the contralateral tumor that was not treated with Ad.MDA-7 was observed demonstrating the ‘bystander’ tumor killing activity for IL-24 protein. Additional studies have confirmed IL-24 protein-mediated tumor cell killing [6870]. Apart from direct tumor cell killing and inhibiting tumor angiogenesis, additional molecular mechanism contributing to the bystander effect has been the activation of the host immune system, induction of ER stress and generation of ROS [71, 72]. Finally, occurrence of bystander effect in humans diagnosed with cancer and treated with Ad-IL24 was demonstrated in a Phase I clinical trial [73, 74]. Results from the clinical trial showed intratumoral administration of Ad-IL24 (INGN 241) resulted in tumor cell apoptosis both at the treated site and in tumor cells at a distant site.

The results from all of these studies clearly established secreted and circulating IL-24 protein exhibited “bystander effect” both in vitro and in vivo. This unique feature provides the opportunity in using IL-24 both as a gene- and protein-based therapeutic. Additionally, testing IL-24 as a gene therapeutic overcomes the limitations of vector transduction efficiency and does not require the tumor in its entirety to be transfected and express IL-24 for producing observable antitumor activity.

c) Metastasis

The rationale to test IL-24 for its anti-metastatic activity arose from the clinical observation made by Ellerhorst et al. who showed inverse correlation between IL-24 expression, tumor cell invasiveness and disease progression in melanoma [20]. The inhibitory activity of IL-24 on tumor cell metastasis and invasion was first demonstrated by our laboratory using lung cancer as a model [75]. In vitro studies demonstrated Ad-IL24 markedly reduced the cell invasion and migration ability of human H1299 and A549 lung cancer cells [75]. Molecular studies revealed IL-24 inhibited PI3K/Akt, matrix metalloproteinase (MMP)-2 and -9, and focal adhesion kinase (FAK) protein expression. All of these proteins have previously been shown to play a role in tumor cell survival and metastasis [7678]. Additional studies from our laboratory showed IL-24 enhanced E-Cadherin expression, a protein that plays a role in cell-cell contact and adhesion [26]. The inhibitory activity of IL-24 on cell migration and invasion was shown to be independent of tumor cell killing. In vivo, treatment of lung tumor-bearing mice with a cationic lipid-based nanoparticle containing IL-24 plasmid DNA reduced lung metastasis [79]. Follow-up studies from our collaborators laboratory showed IL-24 inhibited the PI3K and Wnt/beta-catenin signaling pathway in breast cancer cells [26]. Both, PI3K-AKT-mTOR pathway and Wnt signaling pathway have been shown to be involved in tumor cell invasion and metastasis [26, 80]. Concurring with our study results were the reports from other laboratories demonstrating IL-24 exhibited antimetastatic activity in pancreatic cancer cells [7678]. All of these findings provide evidence that IL-24 inhibits multiple signaling pathways that are associated with tumor cell metastasis.

More recent studies conducted in our laboratory has revealed IL-24 when expressed at pharmacological levels in human H1299 lung cancer cells inhibited the Akt/mTOR signaling pathway resulting in suppression of the tumor cell migratory function [48]. Expression of myristoylated Akt protein resulted in diminished IL-24 inhibitory activity on cell migration and invasion demonstrating IL-24-mediated anti-metastatic activity occurred by targeting Akt (unpublished data). Investigation into molecular signaling upstream of Akt has revealed IL-24 suppresses the chemokine CXCR4/CXCL12 axis (unpublished data). CXCR4 is upstream of Akt and activation of the CXCR4/CXCL12 results in signal transduction downstream that involves the Akt/mTOR pathway. Studies have demonstrated CXCR4/CXCL-12 signaling is important for cell migration and invasion and contributes to tumor metastasis [8185]. In fact, inhibitors of CXCR4 are currently in clinical testing for lung cancer and other solid tumors. On the basis of our preliminary findings we speculate that IL-24-mediated antimetastatic activity primarily occurs by inhibiting the CXCR4/CXCL12 pathway. Additional preclinical studies are currently being conducted in the laboratory to define how IL-24 regulates CXCR4/CXCL12 and identify the intermediary signaling proteins involved in the cross-talk between CXCR4 and Akt and that might also be modulated by IL-24.

From a clinical perspective, the advantage of using IL-24 as an anticancer drug is that tumor cells often use multiple signaling pathways to escape from the cytotoxic effects of a drug. Additionally, inhibiting one pathway in cancer cells often results in the activation of a redundant or alternate pathway thus resulting in cell survival. Therefore a cocktail therapy would be required. These potential problems are minimized using IL-24 as a therapeutic at least in the preclinical studies where IL-24 inhibited multiple pathways resulting in cell killing and inhibition of metastasis.

d) Angiogenesis

Angiogenesis is a complex process, which involves series of molecular events and signaling cascade including formation of new blood vessels, endothelial cell proliferation, disruption of existing extracellular matrix and formation of new matrix. Angiogenesis is a requirement for normal physiologic conditions. However, under pathological conditions such as in cancer, angiogenesis plays an important role in contributing to tumor growth and development of metastasis [86]. Thus, the concept of antiangiogenic therapy was developed with the hypothesis “inhibiting tumor angiogenesis would deprive tumor cells of nutrients and oxygen” resulting in collapse of blood supply to the tumors resulting in tumor cell death and shrinkage [87, 88]. On the basis of this concept several antiangiogenic agents have been developed and tested with few showing promise in the clinic [8998]. Thus there is a continuum to develop and test new and improved antiangiogenic agents of biological and synthetic origin.

The concept of testing IL-24 for its antiangiogenic activity arose from a serendipitous observation made in our laboratory. Treatment of lung tumor xenograft with Ad-IL24 resulted in tumor growth inhibition that was associated with reduction in number of CD31 positive endothelial cells, a marker indicative of reduced blood vessels in the tumor. This initial observation lead us to ask the question of whether IL-24 inhibited tumor vascularization and the underlying molecular mechanism? In vivo chamber window studies showed Ad-IL24 significantly inhibited neo-angiogenesis [99]. Follow-up studies focused on demonstrating IL-24 protein possessed antiangiogenic activity. Addition of human IL-24 protein to human umbilical vein endothelial cells (HUVEC) and human lung microvascular endothelial cells (HMVEC-L) resulted in a dose-dependent inhibition of endothelial cell differentiation (ECD) but not endothelial cell proliferation [66]. Additionally, IL-24 potently inhibited vascular endothelial growth factor- (VEGF) and basic fibroblast growth factor- (bFGF) induced endothelial cell migration. The IL-24 inhibitory effect on HUVEC and HMVEC was 10–50 times more potent than the inhibitory effects induced by interferon (IFN) –γ, endostatin, and inducible protein (IP)-10 [66]. The inhibitory effect of IL-24 was shown to occur via the IL-22 receptor and a requirement for IL-22R1 subunit expression on endothelial cells was demonstrated. The intracellular signaling that occurs following IL-24 binding to its receptor on endothelial cells remains unknown. This is an area that needs to be investigated in detail for improving our understanding of IL-24 biology and angiogenesis. It is possible that IL-24 inhibits the Akt/mTOR signaling pathway in endothelial cells akin to that observed in the tumor cells. This possibility is likely to occur since in a separate study we showed tissue culture supernatant collected from Ad-IL24-infected tumor cells and rich in secreted IL-24 protein when added to HUVEC cells showed reduced activation of Akt [47, 75]. However, additional mechanistic studies are warranted to dissect the signaling pathway that triggers the inhibitory activity on endothelial cells.

In vivo studies confirmed the in vitro findings and demonstrated IL-24 protein suppressed growth of lung tumor xenograft by inhibiting tumor angiogenesis [75]. In vivo studies showed human embryonic kidney 293 cells (HEK 293) stably transfected and expressing IL-24 (HEK293-IL24) when mixed with human A549 lung tumor cells and implanted into nude mice resulted in suppression of tumor growth when compared to tumor growth in mice implanted with mixture of unmodified parental HEK293 and A549 cells [66]. In addition to tumor growth inhibition, apoptosis of tumor endothelial cells and tumor cells, reduced number of CD31 positive endothelial cells and decreased hemoglobin level were also evident [66]. These findings demonstrated that IL-24 protein directly inhibits tumor angiogenesis and possess antiangiogenic activity. Additionally, IL-24 protein secreted from HEK293-IL24 cells and circulating in serum exhibited “bystander effect” on tumors implanted at a distant site in the mice. In this experiment, A549 lung tumors were implanted in the lower right flank of the nude mice, when the tumors reached the size of 50–100 mm3, HEK293 or HEK293-IL24 cells were implanted subcutaneously in the upper right flank and tumor growth were monitored. A significant delay in tumor growth (40-50% reduction) was observed on both flanks of mice that were implanted with a mixture of tumor cells and HEK 293-IL24. Further, the animals implanted with HEK293-IL24 did not show any toxicity indicating that circulating IL-24 protein had no non-specific toxicity towards normal tissues. Our findings showed that IL-24 protein in blood circulation can produce systemic and direct anticancer activity in vivo.

In a separate study we showed IL-24 can also modulate angiogenesis by suppressing growth factors produced by tumor cells. Our study showed treatment of lung tumor cells with Ad-IL24 resulted in diminished expression of VEGF, IL-8, FGF and transforming growth factor (TGF) mRNA in lung tumor cells [99]. Follow-up study by Nishikawa et al. showed Ad-IL24 inhibited VEGF, bFGF, and IL-8 protein expression in human lung tumor xenografts [100]. Furthermore, combining radiation therapy with Ad-IL24 resulted in greater inhibition of VEGF, bFGF, IL-8 and tumor neovascularization resulting in enhanced antitumor activity. The results from this study concurred with our own findings and suggested IL-24 could also indirectly inhibit tumor angiogenesis by reducing growth factor expression by tumor cells.

Follow-up studies in our laboratory demonstrated IL-24 inhibited VEGF expression in lung and prostate cancer cells through the Src pathway [101]. IL-24 was shown to directly inhibit Src kinase activation resulting in reduced transcription and translation of VEGF. Moreover, conditioned tissue culture supernatant obtained from Ad-IL24 treated tumor cells when added to actively growing HUVEC cells markedly diminished VEGF receptor 2 (VEGFR2)-mediated AKT signaling that resulted in induction of endothelial cell growth arrest and apoptosis [101]. However, these inhibitory effects on HUVEC cells were abrogated on exogenous addition of recombinant VEGF protein to the tissue culture media obtained from Ad-IL24-treated tumor cells. The results from this study showed IL-24 inhibited VEGF expression in tumor cells that resulted in diminished signaling to endothelial cell survival thereby causing an antiangiogenic effect. To further substantiate the findings, we combined Ad-IL24 with the clinically approved antiangiogenic drug, Bevacizumab (Avastin). Bevacizumab is an anti-VEGF antibody that binds and prevents secreted VEGF from binding to its receptor, VEGFR2. In vitro and in vivo studies demonstrated enhanced antitumor activity when Ad-IL24 was combined with Bevacizumab [101]. Molecular studies showed both Ad-IL24 and Bevacizumab treatment reduced VEGF expression levels in tumor cells both in vitro and in vivo. However, combination therapy showed the greatest reduction in VEGF expression. Thus, IL-24 suppresses angiogenesis by inhibiting the expression of growth factors produced by tumor cells.

Results from all of the studies described above clearly establish IL-24 exerts its antiangiogenic activity by direct and indirect mechanism of action on tumor endothelial cells and tumor cells respectively. Although we demonstrated IL-24 activity on VEGF, it is still not known how other growth factors are modulated by IL-24. Additional information obtained by conducting more detailed studies will allow testing of new combination therapies with novel antiangiogenic agents.

Combination therapy

It will be evident from the detailed description provided in the earlier sections that IL-24 is a potent tumor suppressor/cytokine that modulates several signaling pathways that are required for tumor cell survival, metastasis and angiogenesis. Given the plethora of information on IL-24, several laboratories including our own laboratory have tested IL-24-based combination therapies. Treatment of lung tumor cells with Ad-IL24 in combination with radiation downregulated DNA-repair enzymes resulting in enhanced radiation-induced DNA damage in tumor cells and tumor regression [100]. Treatment of human breast cancer xenograft with Ad-IL24 and radiation produced complete tumor regression [102]. Zhao et al. showed the tumor suppressive effect of dual gene therapy (ING4-inhibitor of growth family member 4 and IL-24) combined with radiotherapy in the breast cancer cells [103]. In this study Ad. ING4/IL-24 gene therapy and radiotherapy suppressed cell proliferation and induced apoptosis in breast cancer cells. In another study, Ad-IL24 when combined with cyclooxygenase (COX)-2 inhibitor produced enhanced radiosensitization of breast cancer cells [104]. These findings reveal the advantage and clinical relevance of combining IL-24-based gene therapy with radiotherapy.

Ad-IL24 when combined with non-steroidal anti-inflammatory drug (NSAIDS) such as sulindac suppressed nuclear factor (NF) kappa B resulting in enhanced antitumor activity [105]. Subsequent studies from other laboratories concurred with our findings and demonstrated enhanced antitumor activity when combined with other NSAIDS [45]. Enhanced antitumor activity has also been demonstrated when Ad-IL24 was combined with molecularly targeted antisense oligonucleotides, biologic therapy, antioxidants and other novel agents in various types of cancer cells [106110]. McKenzie et al. showed cytotoxic effects of Ad-IL24 against breast cancer cells was enhanced when combined with Trastuzumab (Herceptin) [111]. Combination of Ad-IL24 and human tumor necrosis factor-alpha (rhTNF) also showed synergistic therapeutic effect in human prostate cancer cells [112]. Similarly, treatment of melanoma cells with Ad-IL24 plus Temozolomide produced greater antitumor activity [113].

Since these early reports showing combining IL-24 with other therapies produced greater antitumor activity, a slew of studies have recently been conducted reporting similar findings. For example, combination of oncolytic adenovirus expressing IL-24 with chemotherapeutic agents dramatically enhanced the cytotoxic effects through induction of apoptosis against cancer of the breast, colon, liver, lung, brain, pancreas, and melanoma [110, 114123]. In yet another study, treatment of hepatocellular carcinoma (HCC) cells in vitro with IFN-alpha in combination with an oncolytic adenovirus expressing IL-24 (SG600-IL-24) resulted in tumor cell apoptosis. Molecular studies showed increase in STAT-1 and SOCS1 protein expression while decrease in the expression of metastatic and angiogenic proteins such as MMP-2, XIAP, OPN and VEGF [124]. In vivo studies showed IFN-alpha plus SG600-IL-24 treatment resulted in significant reduction in tumor growth and increased the survival of mice. All of these studies provide evidence that combining IL-24-based therapy with other therapies will be beneficial and produce maximal antitumor activity with minimal to no toxicity to normal tissues. Combining IL-24 with other treatments will also reduce the treatment doses required thereby circumventing dose-limited toxicity and potentially avoid or delay development of therapy resistance.

Cancer stem cells
The last decade has witnessed several laboratories including our own testing IL-24 as anticancer drug against established in vitro and in vivo tumor models. With the discovery of cancer stem cells (CSCs) or tumor-initiating cells (TICs) and their role in contributing to tumor relapse and therapy resistance [125], emphasis has recently shifted towards testing the antitumor activity of IL-24 on CSCs. A recent study reported CD44+/CD24-/low breast CSCs were susceptible to Ad-IL24 treatment both in vitro and in vivo[126]. No toxicity was observed towards normal stem cells. Additional observations made in this study was Ad-IL24 exhibited “bystander therapeutic effect” on contralateral untreated CSC-induced tumors in mice. Mechanism of CSC death was shown to occur via ER stress-mediated apoptosis as evidenced by the upregulation of BiP/GRP78, GRP94 and GADD153 proteins and activation of eIF2α protein [126]. IL-24 has also been reported to efficiently reduce the proliferation and induce apoptosis in myeloid leukemia cells and in leukemia stem like cells [127, 128]. More recently, studies undertaken in our laboratory showed Ad-IL24 treatment of aldehyde dehydrogenase positive (ALDH+) human lung CSCs reduced the number of tumorospheres (unpublished data; Figure 1). The results from these studies demonstrate IL-24 can efficiently eliminate both tumor cells and CSCs and thus IL-24-based therapy is an attractive therapy option for the treatment of cancer.
Figure 1

IL-24 suppresses tumorosphere formation by lung cancer stem cells. Aldehyde dehydrogenase positive (ALDH+) human lung cancer stem cells (CSCs) when treated with Ad-IL24 showed reduced tumorosphere formation in vitro.

IL-24 mediated cellular signaling - clinical observation

Based on the extensive preclinical data demonstrating the antitumor activities of IL-24, a Phase I clinical trial was initiated to test the maximum tolerated dose (MTD) and toxicity of Ad-IL24 treatment in cancer patients. Secondary end points included biological measurements of transgene expression, molecular markers and tumor cell death. Study results at the end of trial revealed Ad-IL24 therapy was safe and well-tolerated with no untoward treatment-related toxicity observed [73, 74]. Biological assays showed 10% to 30% of the tumor mass was transduced following Ad-IL24 treatment that resulted in 70% of the tumor cells showing signs of apoptosis. Additionally, expression of exogenous IL-24 protein was observed in areas of tumor tissues that were outside and beyond Ad-IL24 injection site suggesting IL-24 protein was secreted that diffused throughout the tumor. These findings support the occurrence of IL-24-mediated bystander antitumor activity, an observation that concurred with preclinical study results [11, 26, 66]. Additionally, increase in tumor necrosis factor-α (TNF-α), IL-6, IL-10, and interferon-γ (IFN-γ) cytokine levels and CD8 positive-T cells were demonstrated in patients treated with Ad-IL24 suggesting activation of the pro-immune response, another observation that was in agreement with preclinical data [72, 73]. Thus, the existence of a strong correlation between preclinical and clinical study results warrant further testing of IL-24-based cancer therapy either as monotherapy or in combination with other therapeutics in the clinic for treatment of human cancers.

Conclusions and future directions

Results from preclinical and clinical studies have established IL-24, a member of the IL-10 super-family, functions as a tumor suppressor/cytokine gene. IL-24 is the only IL-10 family member that exhibits antitumor activity thus separating itself from other family members. Although IL-24 is not a classical tumor suppressor, its ability to inhibit multiple cell signaling pathways that are required for tumor growth, invasion, metastasis and angiogenesis places it in a unique class of anticancer agents (Figure 2). It is also evident that combining with different therapies results in enhanced anticancer activity providing an opportunity for developing IL-24-based personalized therapy for treating patients diagnosed with various types of cancer. Finally, the ability to kill CSCs will likely reduce disease relapse and improve overall five-year survival of cancer patients. Added advantage that is foreseen is that IL-24 therapy will improve the patient’s quality of life as no adverse events or treatment-related toxicity was observed in the clinical trial. Although use of IL-24 as an anticancer drug for treatment of cancer is at the forefront, there are numerous questions that remain unanswered. For example, the IL-24 receptor expression in various tissues and different pathological conditions remains unknown. The fundamental question of why IL-24 protein expression is lost in cancer cells although mRNA is detectable has not been studied. Since IL-24 protein can exert antitumor activity, what are the limitations in producing large quantities of purified IL-24 protein for testing protein-based therapy? Finally, does post-translational modification (PTM) play a role in the IL-24 protein attaining different functional properties such as tumor suppressor function versus cytokine function and also affect intracellular localization? Last but not the least, till date very few studies have focused on IL-24-based systemic therapy. Majority of the studies and examples cited in this article have used intratumoral therapy and have used adenovirus as a gene delivery vehicle. However, clinical experience indicates cancer is often detected in patients when the disease has metastasized requiring systemic therapy. Thus, it is of great importance and of clinical relevance to develop and test delivery vehicles carrying IL-24 gene or IL-24 protein that can be administered systemically and are safe.
Figure 2

Molecular signaling pathways regulated by MDA-7/IL-24 in human cancer cells. Schematic summarizes the findings made in clinical and preclinical studies demonstrating molecular signaling pathways that are regulated by IL-24 thereby inhibiting cancer cell growth, invasion and metastasis.

With the advent of nanotechnology, we are not very far from combining nanotechnology platforms for IL-24-based therapy. Thus, systemic IL-24-based nanotherapy will become a reality in the future and become available for clinical testing.

Declarations

Acknowledgments

The authors thank various members of the laboratory who have made significant contributions in studying the tumor suppressive activity of IL-24 and advancing IL-24-based therapy in clinical testing.

Authors’ Affiliations

(1)
Department of Pathology, Stanton L Young Biomedical Research Center, The University of Oklahoma Health Sciences Center
(2)
Department of Radiation Oncology, University of Oklahoma Health Sciences Center
(3)
The Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center
(4)
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center

References

  1. Huang EY, Madireddi MT, Gopalkrishnan RV, Leszczyniecka M, Su Z, Lebedeva IV, Kang D, Jiang H, Lin JJ, Alexandre D, Chen Y, Vozhilla N, Mei MX, Christiansen KA, Sivo F, Goldstein NI, Mhashilkar AB, Chada S, Huberman E, Pestka S, Fisher PB: Genomic structure, chromosomal localization and expression profile of a novel melonam differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene 2001, 20:7051–7063.PubMedView ArticleGoogle Scholar
  2. Mhashilkar AM, Schrock RD, Hindi M, Liao J, Sieger K, Kourouma F, Zou-Yang XH, Onishi E, Takh O, Vedvick TS, Fanger G, Stewart L, Watson GJ, Snary D, Fisher PB, Saeki T, Roth JA, Ramesh R, Chada S: Melanoma differentiation associated gene-7 (mda-7): a novel anti-tumor gene for cancer gene therapy. Mol Med 2001, 7:271–282.PubMed CentralPubMedGoogle Scholar
  3. Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB: Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 2004, 22:929–979.PubMedView ArticleGoogle Scholar
  4. Jiang H, Fisher PB: Use of a sensitive and efficient subtraction hybridization protocol for the identificationof genes differentially regulated during the induction of differentiation in human melanoma cells. Mol Cell Differ 1993, 1:285–299.Google Scholar
  5. Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB: Subtraction hybridization identifies a novel melanomadifferentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995, 11:2477–2486.PubMedGoogle Scholar
  6. Madireddi MT, Dent P, Fisher PB: Regulation of mda-7 gene expression during human melanoma differentiation. Oncogene 2000, 19:1362–1368.PubMedView ArticleGoogle Scholar
  7. Gupta P, Su ZZ, Lebedeva IV, Sarkar D, Sauane M, Emdad L, Bachelor MA, Grant S, Curiel DT, Dent P, Fisher PB: mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 2006, 111:596–628.PubMed CentralPubMedView ArticleGoogle Scholar
  8. Zhang HG, Wang J, Yang X, Hsu HC, Mountz JD: Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene 2004, 23:2009–2015.PubMedView ArticleGoogle Scholar
  9. Fuson KL, Zheng M, Craxton M, Pataer A, Ramesh R, Chada S, Sutton RB: Structural mapping of post-translational modifications in human interleukin-24: role of N-linked glycosylation and disulfide bonds in secretion and activity. J Biol Chem 2009, 284:30526–30533.PubMedView ArticleGoogle Scholar
  10. Gopalan B, Shanker M, Scott A, Branch CD, Chada S, Ramesh R: MDA-7/IL-24, a novel tumor suppressor/cytokine is ubiquitinated and regulated by the ubiquitin-proteasome system, and inhibition of MDA-7/IL-24 degradation enhances the antitumor activity. Cancer Gene Ther 2008, 15:1–8.PubMedView ArticleGoogle Scholar
  11. Chada S, Mhashilkar AM, Ramesh R, Mumm JB, Sutton RB, Bocangel D, Zheng M, Grimm EA, Ekmekcioglu S: Bystander activity of Ad-mda7: human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. Mol Ther 2004, 10:1085–1095.PubMedView ArticleGoogle Scholar
  12. Lebedeva IV, Sauane M, Gopalkrishnan RV, Sarkar D, Su ZZ, Gupta P, Nemunaitis J, Cunningham C, Yacoub A, Dent P, Fisher FB: mda-7/IL-24: exploiting cancer’s Achilles’ heel. Mol Ther 2005, 11:4–18.PubMedView ArticleGoogle Scholar
  13. Soo C, Shaw WW, Freymiller E, Longaker MT, Bertolami CN, Chiu R, Tieu A, Ting K: Cutaneous rat wounds express c49a, a novel gene with homology to the human melanoma differentiation associated gene, mda-7. J Cell Biochem 1999, 74:1–10.PubMedView ArticleGoogle Scholar
  14. Zhang R, Tan Z, Liang P: Identification of a novel ligand-receptor pair constitutively activated by rasoncogenes. J Biol Chem 2000, 275:24436–24443.PubMedView ArticleGoogle Scholar
  15. Wang M, Tan Z, Zhang R, Kotenko SV, Liang P: Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem 2002, 277:7341–7347.PubMedView ArticleGoogle Scholar
  16. Wang M, Liang P: Interleukin-24 and its receptors. Immunology 2005, 114:166–170.PubMedView ArticleGoogle Scholar
  17. Schaefer G, Venkataraman C, Schindler U: Cutting edge: FISP (IL-4-induced secreted protein), a novelcytokine-like molecule secreted by Th2 cells. J Immunol 2001, 166:5859–5863.PubMedGoogle Scholar
  18. Fisher PB, Sarkar D, Lebedeva IV, Emdad L, Gupta P, Sauane M, Su ZZ, Grant S, Dent P, Curiel DT, Senzer N, Nemunaitis J: Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24): novel gene therapeutic for metastatic melanoma. Toxicol Appl Pharmacol 2007, 224:300–307.PubMed CentralPubMedView ArticleGoogle Scholar
  19. Ishikawa S, Nakagawa T, Miyahara R, Kawano Y, Takenaka K, Yanagihara K, Otake Y, Katakura H, Wada H, Tanaka F: Expression of MDA-7/IL-24 and its clinical significance in resected non-small cell lung cancer. Clin Cancer Res 2005, 11:1198–1202.PubMedView ArticleGoogle Scholar
  20. Ellerhorst JA, Prieto VG, Ekmekcioglu S, Broemeling L, Yekell S, Chada S, Grimm EA: Loss of MDA-7 expression with progression of melanoma. J Clin Oncol 2002, 20:1069–1074.PubMedView ArticleGoogle Scholar
  21. Su ZZ, Madireddi MT, Lin JJ, Young CS, Kitada S, Reed JC, Goldstein NI, Fisher P: The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA 1998, 95:14400–14405.PubMedView ArticleGoogle Scholar
  22. Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC: Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 2001, 167:3545–3549.PubMedGoogle Scholar
  23. Conti P, Kempuraj D, Frydas S, Kandere K, Boucher W, Letourneau R, Madhappan B, Sagimoto K, Christodoulou S, Theoharides TC: IL-10 subfamily members: IL-19, IL-20, IL-22, IL-24 and IL-26. Immunol Lett 2003, 88:171–174.PubMedView ArticleGoogle Scholar
  24. Parrish-Novak J, Xu W, Brender T, Yao L, Jones C, West J, Brandt C, Jelinek L, Madden K, McKernan PA, Foster DC, Jaspers S, Chandrasekher YA: Interleukins 19, 20, and 24 signal through two distinctreceptor complexes: differences in receptor–ligand interactions mediate uniquebiological functions. J Biol Chem 2002, 277:47517–47523.PubMedView ArticleGoogle Scholar
  25. Chada S, Sutton RB, Ekmekcioglu S, Ellerhorst J, Mumm JB, Leitner WW, Yang HY, Sahin AA, Hunt KK, Fuson KL, Poìndexter N, Roth JA, Ramesh R, Grimm EA, Mhashilkar AM: MDA-7/IL-24 is a unique cytokine–tumor suppressor in the IL-10 family. Int Immunopharmacol 2004, 4:649–667.PubMedView ArticleGoogle Scholar
  26. Chada S, Bocangel D, Ramesh R, Grimm EA, Mumm JB, Mhashilkar AM, Zheng M: mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer. Mol Ther 2005, 11:724–733.PubMedView ArticleGoogle Scholar
  27. Mao Z, Bian G, Sheng W, He S, Yang J, Dong X: Adenovirus-mediated IL-24 expression enhances the chemosensitivity of multidrug-resistant gastric cancer cells to cisplatin. Oncol Rep 2013, 30:2288–2296.PubMedGoogle Scholar
  28. Sauane M, Lebedeva IV, Su ZZ, Choo HT, Randolph A, Valerie K, Dent P, Gopalkrishnan RV, Fisher PB: Melanoma differentiation associated gene-7/interleukin-24 promotes tumor cell-specific apoptosis through both secretory and nonsecretory pathways. Cancer Res 2004, 64:2988–2993.PubMedView ArticleGoogle Scholar
  29. Saeki T, Mhashilkar A, Chada S, Branch C, Roth JA, Ramesh R: Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro . Gene Ther 2000, 7:2051–2057.PubMedView ArticleGoogle Scholar
  30. Kawabe S, Nishikawa T, Munshi A, Roth JA, Chada S, Meyn RE: Adenovirus-mediated mda-7 gene expression radiosensitizes non-small cell lung cancer cells via P53-independent mechanisms. Mol Ther 2002, 6:637–644.PubMedView ArticleGoogle Scholar
  31. Yacoub A, Mitchell C, Lebedeva IV, Sarkar D, Su ZZ, McKinstry R, Gopalkrishnan RV, Grant S, Fisher PB, Dent P: mda-7 (IL-24) Inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling. Cancer Biol Ther 2003, 2:347–353.PubMedGoogle Scholar
  32. Su ZZ, Lebedeva IV, Sarkar D, Emdad L, Gupta P, Kitada S, Dent P, Reed JC, Fisher PB: Ionizing radiation enhances therapeutic activity of mda-7/IL-24: overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2. Oncogene 2006, 25:2339–2348.PubMedView ArticleGoogle Scholar
  33. Sarkar D, Su ZZ, Lebedeva IV, Sauane M, Gopalkrishnan RV, Valerie K, Dent P, Fisher PB: mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. Proc Natl Acad Sci USA 2002, 99:10054–10059.PubMedView ArticleGoogle Scholar
  34. Sarkar D, Su ZZ, Lebedeva IV, Sauane M, Gopalkrishnan RV, Dent P, Fisher PB: mda-7 (IL-24): signaling and functional roles. Biotechniques 2002, 33:30–39.Google Scholar
  35. Pataer A, Vorburger SA, Barber GN, Chada S, Mhashilkar AM, Zou-Yang H, Stewart AL, Balachandran S, Roth JA, Hunt KK, Swisher SG: Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase (PKR). Cancer Res 2002, 62:2239–2243.PubMedGoogle Scholar
  36. Pataer A, Vorburger SA, Chada S, Balachandran S, Barber GN, Roth JA, Hunt KK, Swisher SG: Melanoma differentiation-associated gene-7 protein physically associates with the double-stranded RNA-activated protein kinase PKR. Mol Ther 2005, 11:717–723.PubMedView ArticleGoogle Scholar
  37. Saito Y, Miyahara R, Gopalan B, Litvak A, Inoue S, Shanker M, Branch CD, Mhashilkar AM, Roth JA, Chada S, Ramesh R: Selective induction of cell cycle arrest and apoptosis in human prostate cancer cells through adenoviral transfer of the melanoma differentiation-associated-7 (mda-7)/interleukin-24 (IL-24) gene. Cancer Gene Ther 2005, 12:238–247.PubMedView ArticleGoogle Scholar
  38. Gopalan B, Litvak A, Sharma S, Mhashilkar AM, Chada S, Ramesh R: Activation of the Fas-FasL signaling pathway by MDA-7/IL-24 kills human ovarian cancer cells. Cancer Res 2005, 65:3017–3024.PubMedGoogle Scholar
  39. Yacoub A, Park MA, Gupta P, Rahmani M, Zhang G, Hamed H, Hanna D, Sarkar D, Lebedeva IV, Emdad L, Sauane M, Vozhilla N, Spiegel S, Koumenis C, Graf M, Curiel DT, Grant S, Fisher PB, Dent P: Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells. Mol Cancer Ther 2008, 7:297–313.PubMed CentralPubMedView ArticleGoogle Scholar
  40. Yacoub A, Gupta P, Park MA, Rhamani M, Hamed H, Hanna D, Zhang G, Sarkar D, Lebedeva IV, Emdad L, Koumenis C, Curiel DT, Grant S, Fisher PB, Dent P: Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1–3 pathway signaling. Mol Cancer Ther 2008, 7:314–329.PubMedView ArticleGoogle Scholar
  41. Lebedeva IV, Su ZZ, Sarkar D, Kitada S, Dent P, Waxman S, Reed JC, Fisher PB: Melanoma differentiation associated gene-7, mda-7/interleukin-24, induces apoptosis in prostate cancer cells by promoting mitochondrial dysfunction and inducing reactive oxygen species. Cancer Res 2003, 63:8138–8144.PubMedGoogle Scholar
  42. Lebedeva IV, Emdad L, Su ZZ, Gupta P, Sauane M, Sarkar D, Staudt MR, Liu SJ, Taher MM, Xiao R, Barral P, Lee SG, Wang D, Vozhilla N, Park ES, Chatman L, Boukerche H, Ramesh R, Inoue S, Chada S, Li R, De Pass AL, Mahasreshti PJ, Dmitriev IP, Curiel DT, Yacoub A, Grant S, Dent P, Senzer N, Nemunaitis JJ, Fisher PB: mda-7/IL-24, novel anticancer cytokine: focus on bystander antitumor, radiosensitization and antiangiogenic properties and overview of the phase I clinical experience. Int J Oncol 2007, 31:985–1007.PubMedGoogle Scholar
  43. Li Y, Zhang H, Zhu X, Feng D, Gong J, Han T: Interleukin-24 induces neuroblastoma SH-SY5Y cell differentiation, growth inhibition, and apoptosis by promoting ROS production. J Interferon Cytokine Res 2013, 33:709–714.PubMedView ArticleGoogle Scholar
  44. Lebedeva IV, Washington I, Sarkar D, Clark JA, Fine RL, Dent P, Curiel DT, Turro NJ, Fisher PB: Strategy for reversing resistance to a single anticancer agent in human prostate and pancreatic carcinomas. Proc Natl Acad Sci USA 2007, 104:3484–3489.PubMedView ArticleGoogle Scholar
  45. Lebedeva IV, Su ZZ, Sarkar D, Gopalkrishnan RV, Waxman S, Yacoub A, Dent P, Fisher PB: Induction of reactive oxygen species renders mutant and wild-type K-ras pancreatic carcinoma cells susceptible to Ad.mda-7- induced apoptosis. Oncogene 2005, 24:585–596.PubMedView ArticleGoogle Scholar
  46. Lee KM, Kang HA, Park M, Lee HY, Song MJ, Ko K, Oh JW, Kang HS: Interleukin-24 suppresses the growth of vascular smooth muscle cells by inhibiting H(2) O(2)-induced reactive oxygen species production. Pharmacology 2012, 90:332–341.PubMedView ArticleGoogle Scholar
  47. Mhashilkar AM, Stewart AL, Sieger K, Yang HY, Khimani AH, Ito I, Saito Y, Hunt KK, Grimm EA, Roth JA, Meyn RE, Ramesh R, Chada S: MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells. Mol Ther 2003, 8:207–219.PubMedView ArticleGoogle Scholar
  48. Panneerselvam J, Shanker M, Jin J, Branch C, Muralidharan R, Wang Q, Munshi A, Rajagopal R: Functional importance of IL-24 phosphorylation in regulating molecular signaling pathways associated with cancer cell survival and metastasis. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6–10; Washington, DC. Philadelphia (PA): AACR. Cancer Res 2013, 73:5249.Google Scholar
  49. Mizushima N: Autophagy: process and function. Genes Dev 2007, 21:2861–2873.PubMedView ArticleGoogle Scholar
  50. Mathew R, Karantza-Wadsworth V, White E: Role of autophagy in cancer. Nat Rev Cancer 2007, 7:961–967.PubMed CentralPubMedView ArticleGoogle Scholar
  51. Inoue S, Shanker M, Miyahara R, Gopalan B, Patel S, Oida Y, Branch CD, Munshi A, Meyn RE, Andreeff M, Tanaka F, Mhashilkar AM, Chada S, Ramesh R: MDA-7/IL-24-based cancer gene therapy: translation from the laboratory to the clinic. Curr Gene Ther 2006, 6:73–91.PubMedView ArticleGoogle Scholar
  52. Dash R, Bhutia SK, Azab B, Su ZZ, Quinn BA, Kegelmen TP, Das SK, Kim K, Lee SG, Park MA, Yacoub A, Rahmani M, Emdad L, Dmitriev IP, Wang XY, Sarkar D, Grant S, Dent P, Curiel DT, Fisher PB: mda-7/IL-24: a unique member of the IL-10 gene family promoting cancer-targeted toxicity. Cytokine Growth Factor Rev 2010, 21:381–391.PubMed CentralPubMedView ArticleGoogle Scholar
  53. Sieger KA, Mhashilkar AM, Stewart A, Sutton RB, Strube RW, Chen SY, Pataer A, Swisher SG, Grimm EA, Ramesh R, Chada S: The tumor suppressor activity of MDA-7/IL-24 is mediated by intracellular protein expression in NSCLC cells. Mol Ther 2004, 9:355–367.PubMedView ArticleGoogle Scholar
  54. Gupta P, Walter MR, Su ZZ, Lebedeva IV, Emdad L, Randolph A, Valerie K, Sarkar D, Fisher PB: BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis. Cancer Res 2006, 66:8182–8191.PubMedView ArticleGoogle Scholar
  55. Dent P, Yacoub A, Hamed HA, Park MA, Dash R, Bhutia SK, Sarkar D, Wang XY, Gupta P, Emdad L, Lebedeva IV, Sauane M, Su ZZ, Rahmani M, Broaddus WC, Young HF, Lesniak MS, Grant S, Curiel DT, Fisher PB: The development of MDA-7/IL-24 as a cancer therapeutic. Pharmacol Ther 2010, 128:375–384.PubMed CentralPubMedView ArticleGoogle Scholar
  56. Park MA, Yacoub A, Sarkar D, Emdad L, Rahmani M, Spiegel S, Koumenis C, Graf M, Curiel DT, Grant S, Fisher PB, Dent P: PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells. Autophagy 2008, 4:513–515.PubMed CentralPubMedGoogle Scholar
  57. Park MA, Walker T, Martin AP, Allegood J, Vozhilla N, Emdad L, Sarkar D, Rahmani M, Graf M, Yacoub A, Koumenis C, Spiegel S, Curiel DT, Voelkel-Johnson C, Grant S, Fisher PB, Dent P: MDA-7/IL-24-induced cell killing in malignant renal carcinoma cells occurs by a ceramide/CD95/PERK-dependent mechanism. Mol Cancer Ther 2009, 8:1280–1291.PubMed CentralPubMedView ArticleGoogle Scholar
  58. Yacoub A, Hamed HA, Allegood J, Mitchell C, Spiegel S, Lesniak MS, Ogretmen B, Dash R, Sarkar D, Broaddus WC, Grant S, Curiel DT, Fisher PB, Dent P: PERK-dependent regulation of ceramide synthase 6 and thioredoxin play a key role in mda-7/IL-24-induced killing of primary human glioblastomamultiforme cells. Cancer Res 2010, 70:1120–1129.PubMed CentralPubMedView ArticleGoogle Scholar
  59. Hamed HA, Yacoub A, Park MA, Eulitt P, Sarkar D, Dimitrie IP, Chen CS, Grant S, Curiel DT, Fisher PB, Dent P: OSU-03012 enhances Ad.7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins. Cancer Biol Ther 2010, 9:526–536.PubMed CentralPubMedView ArticleGoogle Scholar
  60. Hamed HA, Das SK, Sokhi UK, Park MA, Cruickshanks N, Archer K, Ogretmen B, Grant S, Sarkar D, Fisher PB, Dent P: Combining histone deacetylase inhibitors with MDA-7/IL-24 enhances killing of renal carcinoma cells. Cancer Biol Ther 2013, 14:1039–1049.PubMedView ArticleGoogle Scholar
  61. Bhutia SK, Dash R, Das SK, Azab B, Su ZZ, Lee SG, Grant S, Yacoub A, Dent P, Curiel DT, Sarkar D, Fisher PB: Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24. Cancer Res 2010, 70:3667–3676.PubMed CentralPubMedView ArticleGoogle Scholar
  62. Yokoyama T, Miyamoto S, Ramesh R: Interleukin (IL)-24: a regulator of autophagy and apoptosis-mediated programmed cell death. Trends Cell Biol 2010, 5:61–67.Google Scholar
  63. Yang C, Tong Y, Ni W, Liu J, Xu W, Li L, Liu X, Meng H, Qian W: Inhibition of autophagy induced by overexpression of mda-7/interleukin-24 strongly augments the antileukemia activity in vitro and in vivo . Cancer Gene Ther 2010, 17:109–119.PubMedView ArticleGoogle Scholar
  64. Su Z, Emdad L, Sauane M, Lebedeva IV, Sarkar D, Gupta P, James CD, Randolph A, Valerie K, Walter MR, Dent P, Fisher PB: Unique aspects of mda-7/IL-24 antitumor bystander activity: establishing a role for secretion of MDA-7/IL-24 protein by normal cells. Oncogene 2005, 24:7552–7566.PubMedView ArticleGoogle Scholar
  65. Sauane M, Gopalkrishnan RV, Choo HT, Gupta P, Lebedeva IV, Yacoub A, Dent P, Fisher PB: Mechanistic aspects of mda-7/IL-24 cancer cell selectivity analyzed via a bacterial fusion protein. Oncogene 2004, 23:7679–7690.PubMedView ArticleGoogle Scholar
  66. Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Mumm JB, Stewart AL, Boquoi A, Dumoutier L, Grimm EA, Renauld JC, Kotenko S, Chada S: Melanomaa differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 2003, 63:5105–5113.PubMedGoogle Scholar
  67. Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P, Fisher PB: Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc Natl Acad Sci USA 2005, 102:14034–14039.PubMedView ArticleGoogle Scholar
  68. Liu J, Sheng W, Xie Y, Shan Y, Miao J, Xiang J, Yang J: The in vitro and in vivo antitumor activity of adenovirus-mediated interleukin-24 expression for laryngocarcinoma. Cancer Biother Radiopharm 2010, 25:29–38.PubMedView ArticleGoogle Scholar
  69. Zheng M, Bocangel D, Doneske B, Mhashilkar A, Ramesh R, Hunt KK, Ekmekcioglu S, Sutton RB, Poindexter N, Grimm EA, Chada S: Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother 2007, 56:205–215.PubMedView ArticleGoogle Scholar
  70. Mahasreshti PJ, Kataram M, Wu H, Yalavarthy LP, Carey D, Fisher PB, Chada S, Alvarez RD, Haisma HJ, Dent P, Curiel DT: Ovarian cancer targeted adenoviral-mediated mda-7/IL-24 gene therapy. Gynecol Oncol 2006, 100:521–532.PubMedView ArticleGoogle Scholar
  71. Sauane M, Su ZZ, Dash R, Liu X, Norris JS, Sarkar D, Lee SG, Allegood JC, Dent P, Spiegel S, Fisher PB: Ceramide plays a prominent role in MDA-7/IL-24-induced cancer-specific apoptosis. J Cell Physiol 2010, 222:546–555.PubMedGoogle Scholar
  72. Miyahara R, Banerjee S, Kawano K, Efferson C, Tsuda N, Miyahara Y, Ioannides CG, Chada S, Ramesh R: Melanoma differentiation-associated gene-7 (mda-7)/interleukin (IL)-24 induces anticancer immunity in a syngeneic murine model. Cancer Gene Ther 2006, 13:753–761.PubMedView ArticleGoogle Scholar
  73. Tong AW, Nemunaitis J, Su D, Zhang Y, Cunningham C, Senzer N, Netto G, Rich D, Mhashilkar A, Parker K, Coffee K, Ramesh R, Ekmekcioglu S, Grimm EA, Van Wart Hood J, Merritt J, Chada S: Intratumoral injection of INGN 241, a nonreplicatingadenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol Ther 2005, 11:160–172.PubMedView ArticleGoogle Scholar
  74. Cunningham CC, Chada S, Merritt JA, Tong A, Senzer N, Zhang Y, Mhashilkar A, Parker K, Vukelja S, Richards D, Hood J, Coffee K, Nemunaitis J: Clinical and local biological effects of an intratumoral injection of mda-7 (IL24; INGN 241) in patients with advanced carcinoma: a phase I study. Mol Ther 2005, 11:149–159.PubMedView ArticleGoogle Scholar
  75. Ramesh R, Ito I, Gopalan B, Saito Y, Mhashilkar AM, Chada S: Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther 2004, 9:510–518.PubMedView ArticleGoogle Scholar
  76. Barnett SF, Bilodeau MT, Lindsley CW: The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation. Curr Top Med Chem 2005, 5:109–125.PubMedView ArticleGoogle Scholar
  77. Schaller MD: FAK and paxillin: regulators of N-cadherin adhesion and inhibitors of cell migration? J Cell Biol 2004, 166:157–159.PubMedView ArticleGoogle Scholar
  78. Folgueras AR, Pendás AM, Sánchez LM, López-Otín C: Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 2004, 48:411–424.PubMedView ArticleGoogle Scholar
  79. Ramesh R, Ito I, Saito Y, Wu Z, Mhashikar AM, Wilson DR, Branch CD, Roth JA, Chada S: Local and systemic inhibition of lung tumor growth after nanoparticle-mediated mda-7/IL-24 gene delivery. DNA Cell Biol 2004, 23:850–857.PubMedGoogle Scholar
  80. Luu HH, Zhang R, Haydon RC, Rayburn E, Kang Q, Si W, Park JK, Wang H, Peng Y, Jiang W, He TC: Wnt/beta-catenin signaling pathway as a novel cancer drug target. Curr Cancer Drug Targets 2004, 4:653–671.PubMedView ArticleGoogle Scholar
  81. Akashi T, Koizumi K, Tsuneyama K, Saiki I, Takano Y, Fuse H: Chemokine receptor CXCR4 expression and prognosis in patients with metastatic prostate cancer. Cancer Sci 2008, 99:539–542.PubMedView ArticleGoogle Scholar
  82. Yan L, Cai Q, Xu Y: The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis. Clin Cancer Res 2013, 19:4706–4716.PubMedView ArticleGoogle Scholar
  83. Wald O, Shapira OM, Izhar U: CXCR4/CXCL12 axis in non small cell lung cancer (NSCLC) pathologic roles and therapeutic potential. Theranostics 2013, 3:26–33.PubMed CentralPubMedView ArticleGoogle Scholar
  84. Mukherjee D, Zhao J: The role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res 2013, 3:46–57.PubMed CentralPubMedGoogle Scholar
  85. Dai X, Mao Z, Huang J, Xie S, Zhang H: The CXCL12/CXCR4 autocrine loop increases the metastatic potential of non-small cell lung cancer in vitro . Oncol Lett 2013, 5:277–282.PubMed CentralPubMedGoogle Scholar
  86. Folkman J: Fundamental concepts of the angiogenic process. Curr Mol Med 2003, 3:643–651.PubMedView ArticleGoogle Scholar
  87. Heath VL, Bicknell R: Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 2009, 6:395–404.PubMedView ArticleGoogle Scholar
  88. Cook KM, Figg WD: Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin 2010, 60:222–243.PubMed CentralPubMedView ArticleGoogle Scholar
  89. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994, 79:315–328.PubMedView ArticleGoogle Scholar
  90. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997, 88:277–285.PubMedView ArticleGoogle Scholar
  91. Shaheen RM, Davis DW, Liu W, Zebrowski BK, Wilson MR, Bucana CD, McConkey DJ, McMahon G, Ellis LM: Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res 1999, 59:5412–5416.PubMedGoogle Scholar
  92. Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M, Schlessinger J, Ullrich A, Hubbard SR, Blake RA, Fong TA, Strawn LM, Sun L, Tang C, Hawtin R, Tang F, Shenoy N, Hirth KP, McMahon G, Cherrington S: U6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 2000, 60:4152–4160.PubMedGoogle Scholar
  93. Kumar CC, Malkowski M, Yin Z, Tanghetti E, Yaremko B, Nechuta T, Varner J, Liu M, Smith EM, Neustadt B, Presta M, Armstrong L: Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha (v) beta3 and alpha (v) beta5 integrin receptor antagonist. Cancer Res 2001, 61:2232–2238.PubMedGoogle Scholar
  94. Lingen MW, Polverini PJ, Bouck NP: Inhibition of squamous cell carcinoma angiogenesis by direct interaction of retinoic acid with endothelial cells. Lab Invest 1996, 74:476–483.PubMedGoogle Scholar
  95. Voest EE, Kenyon BM, O’Reilly MS, Truitt G, D’Amato RJ, Folkman J: Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 1995, 87:581–586.PubMedView ArticleGoogle Scholar
  96. Singh RK, Gutman M, Bucana CD, Sanchez R, Llansa N, Fidler IJ: Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc Natl Acad Sci USA 1995, 92:4562–4566.PubMedView ArticleGoogle Scholar
  97. Cristofanilli M, Charnsangavej C, Hortobagyi GN: Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov 2002, 1:415–426.PubMedView ArticleGoogle Scholar
  98. Kerr DJ: Targeting angiogenesis in cancer: clinical development of bevacizumab. Nat Clin Pract Oncol 2004, 1:39–43.PubMedView ArticleGoogle Scholar
  99. Saeki T, Mhashilkar A, Swanson X, Zou-Yang XH, Sieger K, Kawabe S, Branch CD, Zumstein L, Meyan RE, Roth JA, Chada S, Ramesh R: Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo . Oncogene 2002, 21:4558–4566.PubMedView ArticleGoogle Scholar
  100. Nishikawa T, Ramesh R, Munshi A, Chada S, Meyn RE: Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. Mol Ther 2004, 9:818–828.PubMedView ArticleGoogle Scholar
  101. Inoue S, Branch CD, Gallick GE, Chada S, Ramesh R: Inhibition of Src kinase activity by Ad-mda7 suppresses vascular endothelial growth factor expression in prostate carcinoma cells. Mol Ther 2005, 12:707–715.PubMedView ArticleGoogle Scholar
  102. Chada S, Mhashilkar AM, Liu Y, Nishikawa T, Bocangel D, Zheng M, Vorburger SA, Pataer A, Swisher SG, Ramesh R, Kawase K, Meyn RE, Hunt KK: mda-7 gene transfer sensitizes breast carcinoma cells to chemotherapy, biologic therapies and radiotherapy: correlation with expression of bcl-2 family members. Cancer Gene Ther 2006, 13:490–502.PubMedView ArticleGoogle Scholar
  103. Zhao Y, Li Z, Sheng W, Miao J, Yang J: Radiosensitivity by ING4-IL-24 bicistronic adenovirus-mediated gene cotransfer on human breast cancer cells. Cancer Gene Ther 2013, 20:38–45.PubMedView ArticleGoogle Scholar
  104. Suh YJ, Chada S, McKenzie T, Liu Y, Swisher SG, Lucci A, Hunt KK: Synergistic tumoricidal effect between celecoxib and adenoviral-mediated delivery of mda-7 in human breast cancer cells. Surgery 2005, 138:422–430.PubMedView ArticleGoogle Scholar
  105. Oida Y, Gopalan B, Miyahara R, Inoue S, Branch CD, Mhashilkar AM, Lin E, Bekele BN, Roth JA, Chada S, Ramesh R: Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer. Mol Cancer Ther 2005, 4:291–304.PubMedGoogle Scholar
  106. Zhao Y, Li Z, Sheng W, Miao J, Yang J: Adenovirus-mediated ING4/IL-24 double tumor suppressor gene co-transfer enhances antitumor activity in human breast cancer cells. Oncol Rep 2012, 28:1315–1324.PubMedGoogle Scholar
  107. Xu Y, Zhang F, Qin L, Miao J, Sheng W, Xie Y, Xu X, Yang J, Qian H: Enhanced in-vitro and in-vivo suppression of A375 melanoma by combined IL-24/OSM adenoviral-mediated gene therapy. Melanoma Res 2014, 24:20–31.PubMedView ArticleGoogle Scholar
  108. Lebedeva IV, Su ZZ, Vozhilla N, Chatman L, Sarkar D, Dent P, Athar M, Fisher PB: Mechanism of in vitro pancreatic cancer cell growth inhibition by melanoma differentiation-associated gene-7/interleukin-24 and perillyl alcohol. Cancer Res 2008, 68:7439–7447.PubMed CentralPubMedView ArticleGoogle Scholar
  109. Lebedeva IV, Su ZZ, Vozhilla N, Chatman L, Sarkar D, Dent P, Athar M, Fisher PB: Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis. Mol Cancer Ther 2008, 7:2042–2050.PubMedView ArticleGoogle Scholar
  110. Xiao L, Li X, Niu N, Qian J, Xie G, Wang Y: Dichloroacetate (DCA) enhances tumor cell death in combination with oncolytic adenovirus armed with MDA-7/IL-24. Mol Cell Biochem 2010, 340:31–40.PubMedView ArticleGoogle Scholar
  111. McKenzie T, Liu Y, Fanale M, Swisher SG, Chada S, Hunt KK: Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu-overexpressing breast cancer cells. Surgery 2004, 136:437–442.PubMedView ArticleGoogle Scholar
  112. Ramesh R, Chada S: Cancer gene therapy and tumor suppressor genes. Minerva Biotech 2005, 17:93–103.Google Scholar
  113. Zheng M, Bocangel D, Ramesh R, Ekmekcioglu S, Poindexter N, Grimm EA, Chada S: Interleukin-24 overcomes temozolomide resistance and enhances cell death by down-regulation of O6-methylguanine-DNA methyltransferase in human melanoma cells. Mol Cancer Ther 2008, 7:3842–3851.PubMed CentralPubMedView ArticleGoogle Scholar
  114. Fang L, Cheng Q, Bai J, Qi YD, Liu JJ, Li LT, Zheng JN: Anoncolytic adenovirus expressing interleukin-24 enhances antitumor activities in combination with paclitaxel in breast cancer cells. Mol Med Rep 2013, 8:1416–1424.PubMedGoogle Scholar
  115. Jiang G, Jiang AJ, Cheng Q, Tian H, Li LT, Zheng JN: A dual-regulated oncolytic adenovirus expressing interleukin-24 sensitizes melanoma cells to temozolomide via the induction of apoptosis. Tumour Biol 2013, 34:1263–1271.PubMedView ArticleGoogle Scholar
  116. Xu J, Mo Y, Wang X, Liu J, Zhang X, Wang J, Hu L, Yang C, Chen L, Wang Y: Conditionally replicative adenovirus-based mda-7/IL-24 expression enhances sensitivity of colon cancer cells to 5-fluorouracil and doxorubicin. J Gastroenterol 2013, 48:203–213.PubMedView ArticleGoogle Scholar
  117. Jiang G, Zhang K, Jiang AJ, Xu D, Xin Y, Wei ZP, Zheng JN, Liu YQ: A conditionally replicating adenovirus carrying interleukin-24 sensitizes melanoma cells to radiotherapy via apoptosis. Mol Oncol 2012, 6:383–391.PubMedView ArticleGoogle Scholar
  118. Cai Y, Liu X, Huang W, Zhang K, Liu XY: Synergistic antitumor effect of TRAIL and IL-24 with complete eradication of hepatoma in the CTGVT-DG strategy. Acta Biochim Biophys Sin 2012, 44:535–543.PubMedView ArticleGoogle Scholar
  119. Dash R, Azab B, Quinn BA, Shen X, Wang XY, Das SK, Rahmani M, Wei J, Hedvat M, Dent P, Dmitriev IP, Curiel DT, Grant S, Wu B, Stebbins JL, Pellecchia M, Reed JC, Sarkar D, Fisher PB: Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. Proc Natl Acad Sci 2011, 108:8785–8790.PubMedView ArticleGoogle Scholar
  120. Jiang G, Liu YQ, Wei ZP, Pei DS, Mao LJ, Zheng JN: Enhanced anti-tumor activity by the combination of a conditionally replicating adenovirus mediated interleukin-24 and dacarbazine against melanoma cells via induction of apoptosis. Cancer Lett 2010, 294:220–228.PubMedView ArticleGoogle Scholar
  121. Zhong S, Yu D, Wang Y, Qiu S, Wu S, Liu XY: An armed oncolytic adenovirus ZD55-IL-24 combined with ADM or DDP demonstrated enhanced antitumor effect in lung cancer. Acta Oncol 2010, 49:91–99.PubMedView ArticleGoogle Scholar
  122. Kaliberova LN, Krendelchtchikova V, Harmon DK, Stockard CR, Petersen AS, Markert JM, Gillespie GY, Grizzle WE, Buchsbaum DJ, Kaliberov SA: CRAdRGDflt-IL24 virotherapy in combination with chemotherapy of experimental glioma. Cancer Gene Ther 2009, 16:794–805.PubMedView ArticleGoogle Scholar
  123. Wu YM, Zhang KJ, Yue XT, Wang YQ, Yang Y, Li GC, Li N, Wang YG: Enhancement of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying MDA-7/IL-24. Acta Pharmacol Sin 2009, 30:467–477.PubMedView ArticleGoogle Scholar
  124. Wang CJ, Xiao CW, You TG, Zheng YX, Gao W, Zhou ZQ, Chen J, Xue XB, Fan J, Zhang H: Interferon-alpha enhances antitumor activities of oncolytic adenovirus-mediated IL-24 expression in hepatocellular carcinoma. Mol Cancer 2012, 11:31–43.PubMed CentralPubMedView ArticleGoogle Scholar
  125. Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB: Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 2009, 8:806–823.PubMedView ArticleGoogle Scholar
  126. Bhutia SK, Das SK, Azab B, Menezes ME, Dent P, Wang XY, Sarkar D, Fisher PB: Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24. Int J Cancer 2013, 133:2726–2736.PubMedGoogle Scholar
  127. Singh R, Fröbel J, Cadeddu RP, Bruns I, Schroeder T, Brünnert D, Wilk CM, Zerbini LF, Haas R, Czibere A: The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells. Ann Hematol 2012, 91:173–181.PubMedView ArticleGoogle Scholar
  128. Rahmani M, Mayo M, Dash R, Sokhi UK, Dmitriev IP, Sarkar D, Dent P, Curiel DT, Fisher PB, Grant S: Melanoma differentiation associated gene-7/interleukin-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by endoplasmic reticulum stress. Mol Pharmacol 2010, 78:1096–1104.PubMedView ArticleGoogle Scholar

Copyright

© Panneerselvam et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement