Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of YAP

// Yu Tian 1 , Bo Tang 2 , Chengye Wang 1 , Deguang Sun 1 , Rixin Zhang 1 , Nan Luo 3 , Zhao Han 1 , Rui Liang 1 , Zhenming Gao 1 , Liming Wang 1 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China 2 Department of Hepatobiliary Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P.R. China 3 Department of Infection, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China Correspondence to: Liming Wang, email: wangbcc259@163.com Bo Tang, email: dytangbo@163.com Keywords: metformin, hepatocellular carcinoma, 5-fluorouracil, YAP Received: March 30, 2016      Accepted: May 29, 2016      Published: June 15, 2016 ABSTRACT 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.