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

Zhen Cai, Chien Feng Li, Fei Han, Chunfang Liu, Anmei Zhang, Che Chia Hsu, Danni Peng, Xian Zhang, Guoxiang Jin, Abdol Hossein Rezaeian, Guihua Wang, Weina Zhang, Bo Syong Pan, Chi Yun Wang, Yu Hui Wang, Shih Ying Wu, Shun Chin Yang, Fang Chi Hsu, Ralph B. D'Agostino, Christina M. FurduiGregory L. Kucera, John S. Parks, Floyd H. Chilton, Chih Yang Huang, Fuu Jen Tsai, Boris Pasche, Kounosuke Watabe, Hui Kuan Lin

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)263-278.e7
JournalMolecular cell
Volume80
Issue number2
DOIs
StatePublished - Oct 15 2020
Externally publishedYes

Keywords

  • AMPK
  • PDHA
  • TCA cycle
  • breast cancer
  • cancer metastasis
  • metabolic stress

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis'. Together they form a unique fingerprint.

Cite this