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

Publication ,  Journal Article
Cai, Z; Li, C-F; Han, F; Liu, C; Zhang, A; Hsu, C-C; Peng, D; Zhang, X; Jin, G; Rezaeian, A-H; Wang, G; Zhang, W; Pan, B-S; Wang, C-Y ...
Published in: Mol Cell
October 15, 2020

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.

Duke Scholars

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Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

October 15, 2020

Volume

80

Issue

2

Start / End Page

263 / 278.e7

Location

United States

Related Subject Headings

  • Survival Analysis
  • Stress, Physiological
  • Signal Transduction
  • Pyruvate Dehydrogenase Complex
  • Phosphoserine
  • Phosphorylation
  • Neoplasm Metastasis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Humans
 

Citation

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Cai, Z., Li, C.-F., Han, F., Liu, C., Zhang, A., Hsu, C.-C., … Lin, H.-K. (2020). Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis. Mol Cell, 80(2), 263-278.e7. https://doi.org/10.1016/j.molcel.2020.09.018
Cai, Zhen, Chien-Feng Li, Fei Han, Chunfang Liu, Anmei Zhang, Che-Chia Hsu, Danni Peng, et al. “Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis.Mol Cell 80, no. 2 (October 15, 2020): 263-278.e7. https://doi.org/10.1016/j.molcel.2020.09.018.
Cai Z, Li C-F, Han F, Liu C, Zhang A, Hsu C-C, et al. Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis. Mol Cell. 2020 Oct 15;80(2):263-278.e7.
Cai, Zhen, et al. “Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis.Mol Cell, vol. 80, no. 2, Oct. 2020, pp. 263-278.e7. Pubmed, doi:10.1016/j.molcel.2020.09.018.
Cai Z, Li C-F, Han F, Liu C, Zhang A, Hsu C-C, Peng D, Zhang X, Jin G, Rezaeian A-H, Wang G, Zhang W, Pan B-S, Wang C-Y, Wang Y-H, Wu S-Y, Yang S-C, Hsu F-C, D’Agostino RB, Furdui CM, Kucera GL, Parks JS, Chilton FH, Huang C-Y, Tsai F-J, Pasche B, Watabe K, Lin H-K. Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis. Mol Cell. 2020 Oct 15;80(2):263-278.e7.
Journal cover image

Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

October 15, 2020

Volume

80

Issue

2

Start / End Page

263 / 278.e7

Location

United States

Related Subject Headings

  • Survival Analysis
  • Stress, Physiological
  • Signal Transduction
  • Pyruvate Dehydrogenase Complex
  • Phosphoserine
  • Phosphorylation
  • Neoplasm Metastasis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Humans