Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of YAP
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Yu Tian1, Bo Tang2, Chengye Wang1, Deguang Sun1, Rixin Zhang1, Nan Luo3, Zhao Han1, Rui Liang1, Zhenming Gao1, Liming Wang1
1Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
2Department of Hepatobiliary Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P.R. China
3Department of Infection, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
Liming Wang, email: [email protected]
Bo Tang, email: [email protected]
Keywords: metformin, hepatocellular carcinoma, 5-fluorouracil, YAP
Received: March 30, 2016 Accepted: May 29, 2016 Published: June 15, 2016
Metformin plays an anti-proliferative role in tumor cells in many types of cancer. However, the correlation between metformin and sensitivity to chemotherapeutic agents in hepatocellular carcinoma (HCC) and the relevant mechanism are unclear. The present study showed that HCC patients with type 2 diabetes mellitus benefited from metformin administration, with a longer overall survival. Metformin resensitized Bel-7402/5-fluorouracil (Bel/Fu) cells to 5-fluorouracil (5-Fu) in vitro and in vivo, and the combination of metformin and 5-Fu inhibited cell proliferation, promoted cell apoptosis and induced G0/G1 cell cycle arrest in the Bel/Fu cells. Moreover, metformin repressed YAP by both decreasing the total protein expression and accelerating the phosphorylation of YAP. The inhibition of YAP subsequently promoted the expression of PTEN, and suppressed the Akt pathway. Therefore, the expression of P-gp and MRP1 was downregulated. Taken together, our findings suggested that metformin may increase sensitivity to chemotherapeutic agents by suppressing YAP in hepatocellular carcinoma.
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