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Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis #MMPMID33022274
Cai Z; Li CF; Han F; Liu C; Zhang A; Hsu CC; Peng D; Zhang X; Jin G; Rezaeian AH; Wang G; Zhang W; Pan BS; Wang CY; Wang YH; Wu SY; Yang SC; Hsu FC; D'Agostino RB Jr; Furdui CM; Kucera GL; Parks JS; Chilton FH; Huang CY; Tsai FJ; Pasche B; Watabe K; Lin HK
Mol Cell 2020[Oct]; 80 (2): 263-278.e7 PMID33022274show ga
Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
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Mol+Cell 2020 ; 80 (2): 263-278.e7
