Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

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

doi:10.1016/j.gendis.2023.05.022

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Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

Full-length article | 更新时间：2024-02-04

- Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer
- Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer
- Genes & Diseases 2024年11卷第3期
- 作者机构：
  
  1. Department of Oncology, Mayo Clinic,MN,Rochester,USA,55905
  2. 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,China,100021
  3. Department of Dermatology, University of California San Diego,CA,San Diego,USA,92093
  4. Department of General Surgery, Zhongshan Hospital, Fudan University,Shanghai,China,200032
  5. Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine,Shanghai,China,200080
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2023.05.022
  中图分类号：
- 纸质出版日期：2024，
  
  网络出版日期：2024-5-1，
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Xin Xu, Yuan Fang, Somaira Nowsheen, 等. Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer[J]. Genes & Diseases, 2024,11(3).

Xin Xu, Yuan Fang, Somaira Nowsheen, et al. Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer[J]. Genes & Diseases, 2024,11(3).
Xin Xu, Yuan Fang, Somaira Nowsheen, 等. Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer[J]. Genes & Diseases, 2024,11(3). DOI： 10.1016/j.gendis.2023.05.022.

Xin Xu, Yuan Fang, Somaira Nowsheen, et al. Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer[J]. Genes & Diseases, 2024,11(3). DOI： 10.1016/j.gendis.2023.05.022.

摘要

Abstract

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.

关键词

Keywords

AMPK activityCellular metabolic switchECM stiffnessHippo kinase signalingPancreatic ductal adenocarcinoma

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