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    Paradoxical activation of AMPK by glucose drives proliferation in colorectal cancer cells

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    Team Benoit Viollet

    Paradoxical activation of AMPK by glucose drives proliferation in colorectal cancer cells

     

    Benoit Viollet's team in collaboration with the laboratory of  Custodia García-Jiménez (University Rey Juan Carlos, Madrid, Spain) in an article published in the journal PLOS Biology, revealed that the AMPK energy metabolism sensor controls cell proliferation by regulating the activity of the acetyl transferase EP300 in colorectal cancer, with implications for anti-cancer drugs targeting AMPK.

     

    Continuous proliferation of cancer cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. AMP-activated protein kinase (AMPK), the main energy sensor and master regulator of cellular metabolism and bioenergetics, represents a key modulator of cancer cell metabolic plasticity. During periods of energy stress (increase in the cellular AMP/ATP ratio), activation of AMPK confers a function of metabolic checkpoint and proliferation of cancer cells can be shut down by activating AMPK. However, within some cancer cells, a cross-talk with AMPK signaling can also occur to allow proliferation Thus, the determination of the role of AMPK in metabolic reprograming of cancer cells may help to identify the selective molecular targets for efficient anti-cancer therapies.

     

    Contrary to expectations, the authors have found that in colon cancer cells, but not other cancer types, AMPK is activated in response to glucose to drive EP300 activity towards β-catenin target genes to promote colorectal cancer proliferation. It was discovered that glucose metabolism activates AMPK via reactive oxygen species (ROS), but this only occurs in colon cancer cells that are unable to store glucose as glycogen, a more complex carbohydrate. In non-colon cancer types the ability to make glycogen suppresses ROS-mediated activation of AMPK in response to glucose. Importantly, normal colon cells do make glycogen, but this ability is lost during tumor evolution allowing glucose to activate AMPK and drive proliferation via EP300. 

     

     

    Importantly, the clinical relevance of the ROS/AMPK/EP300/β-catenin axis was examined in human samples showing a positive correlation between glycogen content, ROS levels, AMPK activation, EP300 stabilization and increased expression of β-catenin to promote a pro-proliferative gene expression program.

     

    Given the importance of drugs, such as metformin, targeting AMPK in diabetes and cancer, the differential ability of cells to store glucose as glycogen may guide the future choice of AMPK targeting therapies for specific cancer sub-types. 

     

     

    Figure legend: Clinical relevance of the ROS/AMPK/EP300/β-catenin axis in human colorectal cancer. Representative photographs of glycogen content stained with PAS in relation with ROS levels (ROS (8-OHdG)), AMPK activation (pAMPK (T172)), EP300 stabilization (pEP300 (S89)), and β-catenin expression by immunohistochemical analysis in tumor versus healthy human bowel sections.

     

     

     

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    Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer. Gutiérrez-Salmerón M, García-Martínez JM, Martínez-Useros J, Fernández-Aceñero MJ, Viollet B, Olivier S, Chauhan J, Lucena SR, De la Vieja A, Goding CR, Chocarro-Calvo A, García-Jiménez C. PLoS Biol. 2020 Jun 30;18(6):e3000732. 

    doi: 10.1371/journal.pbio.3000732. eCollection 2020 Jun. PMID: 32603375

     

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