Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer
作者机构：State Key Laboratory of Molecular Oncology and Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of General SurgeryShanghai General HospitalShanghai Jiaotong University School of MedicineShanghai 200080China Department of General SurgeryZhongshan HospitalFudan UniversityShanghai 200032China Department of DermatologyUniversity of California San DiegoSan DiegoCA 92093USA Department of OncologyMayo ClinicRochesterMN 55905USA
出 版 物：《Genes & Diseases》 (基因与疾病（英文）)
年 卷 期：2024年第11卷第3期
页 面：338-350页
核心收录：
学科分类：0710[理学-生物学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：supported in part by grants from the Natural Science Foundation of China(No.82272757) CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-067) Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2021-RC310-013) Mayo Foundation,and Beijing Hope Run Special Fund of Cancer Foundation of China(No.LC2021R02)
主 题：AMPKactivity Cellularmetabolic switch ECM stiffness Hippokinase signaling Pancreaticductal adenocarcinoma
摘 要：The adenosine monophosphate(AMP)-activated protein kinase(AMPK)sits at a cen-tral node in the regulation of energy metabolism and tumor *** is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy *** studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic *** this study,we report that AMPK is also highly sensitive to extracellular matrix(ECM)*** 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 *** regulation of AMPK requires the Hippo kinases but not LKB1/*** kinases directly phosphorylate AMPKa at Thr172 to activate AMPK at low ECM ***,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ECM stiffness and is associated with a poor survival *** activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC ***,these findings establish a novel model for AMPK regulation by the mechanical 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.
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