Metformin inhibits the growth of pancreatic cancer cells by inducing degradation of mutant p53 protein

Abstract Pancreatic cancer is one of the most lethal malignant tumors, which usually carries p53 gene mutation. Metformin has been reported to lower the risk of pancreatic cancer among diabetics. However, the underlying mechanism of the anti-tumor effects of metformin in pancreatic cancer is not fully elucidated. In our study, we observed that metformin had anti-tumor effects on pancreatic cancer cells with mutation of p53 gene. After administration of metformin in vitro, the cell cycle was induced to arrest at G0/G1 phase and apoptosis was significantly increased in PANC-1 and BxPc-3 cells. Meanwhile, the activity of SIRT1 was enhanced by metformin, resulting in the deacetylation and degradation of mutant p53 protein. Notably, knockdown of mutant p53 had similar effects to metformin, which inhibited the tumor growth and alleviated the suppression of p53 target genes in pancreatic cancer cells. Furthermore, we demonstrated that metformin regulated the deacetylase activity of SIRT1 through AMPK and mTOR signaling pathways, which was the underlying molecular mechanism for its anti-tumor effects. These results provide new evidence that the anti-tumor effects of metformin may exert by inducing the degradation of mutant p53 in pancreatic cancer cells.