YAP Inhibition by Resveratrol via Activation of AMPK Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine.
Resveratrol, a natural polyphenol present in most plants, inhibits the growth of numerous cancers both in vitro and in vivo. Aberrant expression of YAP has been reported to activate multiple growth-regulatory pathways and confer anti-apoptotic abilities to many cancer cells. However, the role of resveratrol in YES-activated protein (YAP) expression and that of YAP in pancreatic cancer cells' response to gemcitabine resistance remain elusive. In this study, we found that resveratrol suppressed the proliferation and cloning ability and induced the apoptosis of pancreatic cancer cells. These multiple biological effects might result from the activation of AMP-activation protein kinase (AMPK) (Thr172) and, thus, the induction of YAP cytoplasmic retention, Ser127 phosphorylation, and the inhibition of YAP transcriptional activity by resveratrol. YAP silencing by siRNA or resveratrol enhanced the sensitivity of gemcitabine in pancreatic cancer cells. Taken together, these findings demonstrate that resveratrol could increase the sensitivity of pancreatic cancer cells to gemcitabine by inhibiting YAP expression. More importantly, our work reveals that resveratrol is a potential anticancer agent for the treatment of pancreatic cancer, and YAP may serve as a promising target for sensitizing pancreatic cancer cells to chemotherapy.
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. jiang.19900708@stu.xjtu.edu.cn.
Zhengdong
Z
Jiang
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. chenxin.77@stu.xjtu.edu.cn.
Xin
X
Chen
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. ck532128@stu.xjtu.edu.cn.
Ke
K
Chen
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. sunliankang@stu.xjtu.edu.cn.
Liankang
L
Sun
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. gaoluping@stu.xjtu.edu.cn.
Luping
L
Gao
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. trytofly@stu.xjtu.edu.cn.
Cancan
C
Zhou
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. leimeng7@stu.xjtu.edu.cn.
Meng
M
Lei
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. 0556029@fudan.edu.cn.
Wanxing
W
Duan
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. zheng.wang11@mail.xjtu.edu.cn.
Zheng
Z
Wang
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. qyma56@xjtu.edu.cn.
Qingyong
Q
Ma
Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. jgma86@xjtu.edu.cn.
Jiguang
J
Ma
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000093542:Gemcitabine
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D013267:Stilbenes; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D003841:Deoxycytidine; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol; D000093542:Gemcitabine
AMPK; YAP; gemcitabine; pancreatic cancer; resveratrol
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