Malate targets pyruvate kinase M2 to promote colorectal cancer cell cycle arrest and tumor suppression

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To survive nutrient stress caused by rapid proliferation and dysfunctional vasculature, tumor cells extensively reprogram their metabolic pathways, including the tricarboxylic acid (TCA) cycle representing a critical remodeling node. Functioning as a key TCA cycle intermediate, malate bridges fumarate and oxaloacetate, both of which are metabolites known to play significant roles in tumorigenesis. However, whether malate itself regulates tumor progression and the specific mechanism remain unclear. In this study, we demonstrate that oral administration of malate significantly inhibits the growth of colorectal cancer (CRC) xenografts in both nude mice and immunocompetent models, suggesting its antitumor effects are immunity-independent. Mechanistically, we found that malate acts as an allosteric regulator of pyruvate kinase M2 (PKM2), binding to it and initiating a cascade that promotes the ubiquitin-mediated proteasomal degradation of cell division cycle 25 A (CDC25A). This reduction in CDC25A enhances the inhibitory phosphorylation of CDK1 at Tyr15, leading to cell cycle arrest and suppression of proliferation. Clinical analyses further support these findings, showing decreased malate levels in human CRC tissues. Moreover, the expression of malate-metabolizing enzymes, MDH1 and FH, is significantly correlated with activity of the CDC25A/p-CDK1 signaling axis. Collectively, our results identify malate as a non-metabolic regulator of the cell cycle, operating through the PKM2-CDC25A-CDK1 pathway, and propose a novel therapeutic strategy targeting metabolic mediators of cell proliferation in cancer.

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