首页|Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

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The adenosine monophosphate(AMP)-activated protein kinase(AMPK)sits at a cen-tral node in the regulation of energy metabolism and tumor progression.AMPK is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy stores.Previous studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic cancer.In this study,we report that AMPK is also highly sensitive to extracellular matrix(ECM)stiffness.We found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM stiffness.This regulation of AMPK requires the Hippo kinases but not LKB1/CaMKKβ.Hippo kinases directly phosphorylate AMPKα at Thr172 to activate AMPK at low ECM stiffness.Furthermore,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ECM stiffness and is associated with a poor survival outcome.The activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC growth.Together,these findings establish a novel model for AMPK regulation by the me-chanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.

AMPK activityCellular metabolic switchECM stiffnessHippo kinase signalingPancreatic ductal adenocarcinoma

Xin Xu、Yuan Fang、Somaira Nowsheen、Ye-Xiong Li、Zhenkun Lou、Min Deng

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State Key Laboratory of Molecular Oncology and Department of Radiation Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China

Department of General Surgery,Shanghai General Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200080,China

Department of General Surgery,Zhongshan Hospital,Fudan University,Shanghai 200032,China

Department of Dermatology,University of California San Diego,San Diego,CA 92093,USA

Department of Oncology,Mayo Clinic,Rochester,MN 55905,USA

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国家自然科学基金Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical SciencesNonprofit Central Research Institute Fund of Chinese Academy of Medical SciencesMayo Foundation,and Beijing Hope Run Special Fund of Cancer Foundation of China

822727572021-12M-1-0672021-RC310-013LC2021R02

2024

10.1016/j.gendis.2023.05.022

基因与疾病(英文)

基因与疾病(英文)

ISSN：
年,卷(期)：2024.11(3)
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