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

Zhen Cai1, Chien-Feng Li2, Fei Han1

  • 1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Molecular Cell
|October 6, 2020
PubMed

Insights

AMPK activation fuels cancer metastasis by enhancing the TCA cycle through PDHc activation. This pathway helps cancer cells survive stressful environments and predicts poor survival in advanced breast cancer.

Area of Science:

  • Metabolic pathways in cancer
  • Cancer cell adaptation
  • Molecular mechanisms of metastasis

Background:

  • Cancer metastasis is a leading cause of cancer mortality.
  • The mechanisms by which cancer cells adapt to secondary microenvironments remain unclear.

Purpose of the Study:

  • To investigate the role of AMPK in cancer metastasis.
  • To elucidate the molecular mechanisms by which cancer cells adapt to metastatic environments.

Main Methods:

  • Utilized mouse metastasis models.
  • Investigated the activation of AMP-activated protein kinase (AMPK) and pyruvate dehydrogenase complex (PDHc).
  • Analyzed phosphorylation events on the PDHc alpha subunit (PDHA) in mitochondrial matrix.

Main Results:

  • AMPK activation in metastasis models promotes cancer metastasis.
  • AMPK activates PDHc, maintaining the tricarboxylic acid (TCA) cycle and adapting cells to metabolic and oxidative stress.
  • The AMPK-PDHc axis is active in advanced breast cancer, correlating with poor metastasis-free survival.
  • AMPK phosphorylates PDHA at S295 and S314, activating PDHc and counteracting inhibitory phosphorylation by PDHKs.

Conclusions:

  • AMPK-mediated PDHA phosphorylation activates PDHc and the TCA cycle.
  • This process empowers cancer cells to adapt to metastatic microenvironments, driving metastasis.
  • The AMPK-PDHc pathway represents a potential therapeutic target for preventing cancer metastasis.
Keywords:
AMPKPDHATCA cyclebreast cancercancer metastasismetabolic stress

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