Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis

• Published in: Molecular cell Vol. 80; no. 2; pp. 263 - 278.e7
• Main Authors: Cai, Zhen, Li, Chien-Feng, Han, Fei, Liu, Chunfang, Zhang, Anmei, Hsu, Che-Chia, Peng, Danni, Zhang, Xian, Jin, Guoxiang, Rezaeian, Abdol-Hossein, Wang, Guihua, Zhang, Weina, Pan, Bo-Syong, Wang, Chi-Yun, Wang, Yu-Hui, Wu, Shih-Ying, Yang, Shun-Chin, Hsu, Fang-Chi, D’Agostino, Ralph B., Furdui, Christina M., Kucera, Gregory L., Parks, John S., Chilton, Floyd H., Huang, Chih-Yang, Tsai, Fuu-Jen, Pasche, Boris, Watabe, Kounosuke, Lin, Hui-Kuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2020
• Subjects: AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; breast cancer; breast neoplasms; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; cancer metastasis; Catalytic Domain; Cell Line, Tumor; Cell Survival; Citric Acid Cycle; Enzyme Activation; enzyme activity; Female; Humans; metabolic stress; metastasis; mice; Mice, Inbred BALB C; Mice, Nude; mitochondria; Neoplasm Metastasis; PDHA; Phosphorylation; Phosphoserine - metabolism; pyruvate dehydrogenase (lipoamide); Pyruvate Dehydrogenase Complex - metabolism; Signal Transduction; Stress, Physiological; Survival Analysis; TCA cycle; tricarboxylic acid cycle; PDHA; AMPK; breast cancer; metabolic stress; TCA cycle; cancer metastasis
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2020.09.018

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. [Display omitted] •AMPKα facilitates TCA cycle by maintaining PDH complex activity•AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex•Activation of AMPKα-PDHA axis promotes tumor lung metastasis•AMPKα-PDHA axis predicts poor metastasis-free survival in breast cancer patients Cai et al. demonstrate that phosphorylation of the catalytic subunit PDHA on Ser295 and S314 by AMPKα is essential for the maintenance of pyruvate dehydrogenase complex activity and TCA cycle. Activation of AMPKα-PDHA axis predicts poor metastasis-free survival in breast cancer patients and facilitates tumor lung metastasis.