ArticleGenes & diseases2024
Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer.
Article in Genes & diseases, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Mechanical Cues Regulate Cargo Sorting and Export at the Golgi.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The interplay between extracellular matrix remodeling and cellular lipid metabolic reprogramming in cancer: a review.Molecular biology reports · 2025Review
- Caulerpin Delivery via Pluronic-Free Cubosomes: Unlocking the Therapeutic Potential of a Pigment from an Invasive Marine Algae.Molecular pharmaceutics · 2025Article
- Phosphorylation of USP32 by CDK5 regulates Rap1 stability and therapeutic resistance in pancreatic ductal adenocarcinoma.Oncogene · 2025Article
- Interplay between extracellular matrix mechanics and cell function in mechanobiology.Current opinion in biomedical engineering · 2025Article
- The role of AMPK in pancreatic cancer: from carcinogenesis to treatment.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Review
- Endophilin A2 controls touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking.Military Medical Research · 2024Article
- A stumbling block in pancreatic cancer treatment: drug resistance signaling networks.Frontiers in cell and developmental biology · 2024Review
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.