Proposed model for the mechanism by which metformin mediates cell cycle arrest. Metformin treatment leads to activation of AMPK which leads to loss of cyclin D1 mRNA and downregulation of cyclin D1 protein. The reduction in cyclin D1 results in the release of sequestered cell cycle inhibitors p27Kip1 and p21Cip1. The released CDK inhibitors bind to and inhibit cyclin E/CDK2, thus preventing cell cycle progression from G1 to S phase. In metformin-resistant MDA-MB-231 cells, levels of the CDK inhibitors are insufficient to block CDK2 even though AMPK is active and cyclin D1 is downregulated.