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 ind...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/CaMKKp.Hippo kinases directly phosphorylate AMPKa 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 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.展开更多
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)+1 种基金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).
文摘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/CaMKKp.Hippo kinases directly phosphorylate AMPKa 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 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.
