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

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2020-10

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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.

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Cell Line, Tumor, Animals, Mice, Inbred BALB C, Humans, Mice, Nude, Breast Neoplasms, Neoplasm Metastasis, Pyruvate Dehydrogenase Complex, Phosphoserine, Survival Analysis, Signal Transduction, Cell Survival, Enzyme Activation, Catalytic Domain, Citric Acid Cycle, Phosphorylation, Female, Stress, Physiological, AMP-Activated Protein Kinases

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https://hdl.handle.net/10161/33828

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https://creativecommons.org/licenses/by-nc/4.0

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10.1016/j.molcel.2020.09.018

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Cai, Zhen, Chien-Feng Li, Fei Han, Chunfang Liu, Anmei Zhang, Che-Chia Hsu, Danni Peng, Xian Zhang, et al. (2020). Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis. Molecular cell, 80(2). pp. 263–278.e7. 10.1016/j.molcel.2020.09.018 Retrieved from https://hdl.handle.net/10161/33828.

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Scholars@Duke

Hsu

Che-Chia Hsu

Assistant Professor of Pathology

My research has focused on mitochondrial functions in cancer metabolism and understand the role of mitochondrial dynamics in cellular function and human diseases including cancers. Additionally, I also continuously dissect cancer metabolism and identifying potential metabolic vulnerabilities of cancer initiation, progression and metastasis using several in vitro, ex vivo and in vivo genetical approaches such as CRISPR/Cas9 knockout, mouse/ human organoid cultures and genetically engineered mouse models, thereby characterizing molecular mechanisms regulated by metabolic pathways and developing potential metabolic interventions for targeting cancers. 

Lin

Hui-Kuan Lin

Fred and Janet Sanfilippo Distinguished Professor

The research interest in Dr. Lin lab is to understand oncogenic networks between oncogenes and tumor suppressor genes, dissect the regulatory mechanisms underlying  the crosstalk between ageing and cancer, to unravel the role of posttranslational modifications (PTMs) such as ubiquitination  and metabolism in diverse molecular and biological processes important for cancer progression and metastasis, cancer stem regulation, cancer immunity and drug resistance by using biochemical and molecular approaches along with and genetic mouse models, and finally to develop small molecule inhibitors and antibodies targeting critical oncogenic signaling and metabolic vulnerabilities for cancer treatment. His research goals aim to not only reveal fundamental insights and concepts for cancer biology and cancer immunity, but also develop novel paradigms and therapeutic strategies for targeting human cancer and overcoming drug resistance.

Research interests include:

  • Crosstalk between oncogenic and tumor suppressor networks
  • Posttranslational modifications in signaling and cancer
  • Cancer progression and metastasis
  • Biology of normal and cancer stem cells
  • Metabolism in cancer and ageing

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