Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer
The adenosine monophosphate (AMP)-activated protein kinase (AMPK) sits at a central 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...
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| Format: | Article |
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KeAi Communications Co., Ltd.
2024-05-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304223003057 |
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| author | Xin Xu Yuan Fang Somaira Nowsheen Ye-Xiong Li Zhenkun Lou Min Deng |
| author_facet | Xin Xu Yuan Fang Somaira Nowsheen Ye-Xiong Li Zhenkun Lou Min Deng |
| author_sort | Xin Xu |
| collection | DOAJ |
| description | The adenosine monophosphate (AMP)-activated protein kinase (AMPK) sits at a central 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 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. |
| first_indexed | 2024-03-07T21:44:03Z |
| format | Article |
| id | doaj.art-fdae30568fba45adbe8ce480a0faeb65 |
| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2025-03-22T03:42:31Z |
| publishDate | 2024-05-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj.art-fdae30568fba45adbe8ce480a0faeb652024-04-28T11:49:30ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422024-05-01113101035Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancerXin Xu0Yuan Fang1Somaira Nowsheen2Ye-Xiong Li3Zhenkun Lou4Min Deng5State 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, ChinaDepartment 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, ChinaDepartment of Dermatology, University of California San Diego, San Diego, CA 92093, USAState 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; Corresponding author.Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Corresponding author.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; Corresponding author.The adenosine monophosphate (AMP)-activated protein kinase (AMPK) sits at a central 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 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.http://www.sciencedirect.com/science/article/pii/S2352304223003057AMPK activityCellular metabolic switchECM stiffnessHippo kinase signalingPancreatic ductal adenocarcinoma |
| spellingShingle | Xin Xu Yuan Fang Somaira Nowsheen Ye-Xiong Li Zhenkun Lou Min Deng Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer Genes and Diseases AMPK activity Cellular metabolic switch ECM stiffness Hippo kinase signaling Pancreatic ductal adenocarcinoma |
| title | Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer |
| title_full | Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer |
| title_fullStr | Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer |
| title_full_unstemmed | Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer |
| title_short | Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer |
| title_sort | regulation of ampk activation by extracellular matrix stiffness in pancreatic cancer |
| topic | AMPK activity Cellular metabolic switch ECM stiffness Hippo kinase signaling Pancreatic ductal adenocarcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S2352304223003057 |
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