國家衛生研究院 NHRI:Item 3990099045/16102
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    題名: Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2
    作者: Wang, RH;Chen, PR;Chen, YT;Chen, YC;Chu, YH;Chien, CC;Chien, PC;Lo, SY;Wang, ZL;Tsou, MC;Chen, SY;Chiu, GS;Chen, WL;Wu, YH;Wang, LHC;Wang, WC;Lin, SY;Kung, HJ;Wang, LH;Cheng, HC;Lin, KT
    貢獻者: Institute of Biomedical Engineering and Nanomedicine;Institute of Molecular and Genomic Medicine
    摘要: Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H2S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism. Low level of pyruvate kinase M2 (PKM2) activity in cancer cells is essential for the dependence on aerobic glycolysis. Here the authors show that PKM2 sulfhydration by hydrogen sulfide destabilizes the PKM2 tetramer, leading to reduced PKM2 enzyme activity and enhanced proliferation of breast cancer cells.
    日期: 2024-08-29
    關聯: Nature Communications. 2024 Aug 29;15:Article number 7463.
    Link to: http://dx.doi.org/10.1038/s41467-024-51875-9
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2041-1723&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001301007500002
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85202729087
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