Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of YAP.
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.
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Yu
Y
Tian
Department of Hepatobiliary Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P.R. China.
Bo
B
Tang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Chengye
C
Wang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Deguang
D
Sun
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Rixin
R
Zhang
Department of Infection, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Nan
N
Luo
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Zhao
Z
Han
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Rui
R
Liang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Zhenming
Z
Gao
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China.
Liming
L
Wang
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D016461:Chemoembolization, Therapeutic / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010750:Phosphoproteins / Q000096:biosynthesis; D011379:Prognosis; D014157:Transcription Factors; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D008687:Metformin; D005472:Fluorouracil
5-fluorouracil; YAP; hepatocellular carcinoma; metformin