ArticleMolecular cell2020
Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis.
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Article in Molecular cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 124 papers, 1 of them a synthesis that pooled it.
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124citing papers in PubMed, 1 pooled it
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Who cites it
124 citing papers in PubMed, 1 synthesis or guideline pooled it, 264 citations in OpenAlex.
- Phytochemicals regulate cancer metabolism through modulation of the AMPK/PGC-1α signaling pathway.BMC cancer · 2024Pooled it
- The role of copper and cuproptosis in digestive system cancers: novel therapeutic strategies and mechanistic insights.Cancer biology & therapy · 2026Review
- PDHA1 Hyperactivation-Mediated Glucose Metabolism Reprogramming Fuels Neutrophil NETosis and Promotes Acute Lung Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function.Circulation research · 2026Article
- PCK2 as a potential therapeutic target for aggressive MYC-amplified non-WNT/non-SHH medulloblastoma based on tumor continuum.Acta neuropathologica communications · 2026Article
- From energy metabolic homeostasis to immune remodeling: the role and therapeutic potential of STING signaling in the tumor microenvironment.Cell communication and signaling : CCS · 2026Review
- The pyruvate branch point controls lymphoid cancer cell dissemination.bioRxiv : the preprint server for biology · 2026Article
- Regulation of pyruvate dehydrogenase complex: Dancing to different drums in cancer.International journal of cancer · 2026Review
- Integrative Analysis of Post-Translational Modifications Identifies a PTM-Enriched Regulatory Core in Human Metabolic Enzymes.Metabolites · 2026Article
- PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2.Cell death discovery · 2026Article
- Oblique-incidence reflectivity difference technology identifies the antiviral drug Ribavirin as an inhibitor of lung tumor progression by targeting AMPK signaling.Journal of pharmaceutical analysis · 2026Article
- Prognosis and Immunotherapy Effect of Triple-Negative Breast Cancer by Lactylation-Related Genes and Experimental Validation.Oncology research · 2026Article
- PDHA1 Hyperactivation Orchestrates Metabolic Reprogramming Promoting Endothelial Senescence.Research (Washington, D.C.) · 2026Article
- AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.Nature metabolism · 2026Review
- Cuproptosis-related gene DLD expression correlates with the prognosis and tumor immune microenvironment in clear cell renal cell carcinoma.Discover oncology · 2025Article
- Spermidine Alleviates Sepsis-Induced Acute Lung Injury through AMPK-Mediated Improvement of Necroptosis.Inflammation · 2025Article
- Transcriptomic exploration of key genes related to mitochondria and ferroptosis in inflammatory bowel disease and experimental validation.Scientific reports · 2025Article
- Application value of a prognostic risk model based on lactate-related genes in non-small cell lung cancer.Translational cancer research · 2025Article
- Pregnane X receptor (PXR) as a prognostic marker and therapeutic target in kidney renal clear cell carcinoma (KIRC) via AMPK pathway regulation.Scientific reports · 2025Article
- CD137L promotes immune surveillance in melanoma via HLTF regulation.Nature communications · 2025Article
64 more citing papers are in PubMed but not listed here.
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Authors and funding
28 authors at 5 institutions in 2 countries.
Zhen CaiDepartment 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.
Chien-Feng LiDepartment of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
Fei HanDepartment 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.
Chunfang LiuDepartment 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.
Anmei ZhangDepartment 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.
Che-Chia HsuDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Danni PengDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Xian ZhangDepartment 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.
Guoxiang JinDepartment 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.
Abdol-Hossein RezaeianDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Guihua WangDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Weina ZhangDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Bo-Syong PanDepartment 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.
Chi-Yun WangDepartment 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; International PhD Program in Innovative Technology of Biomedical Engineering and Medical Device, Ming Chi University of Technology, New Taipei City 243303, Taiwan.
Yu-Hui WangDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Shih-Ying WuDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Shun-Chin YangDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Fang-Chi HsuDepartment of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Ralph B D'AgostinoDepartment of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Christina M FurduiDepartment of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Gregory L KuceraDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
John S ParksDepartment of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Floyd H ChiltonDepartment of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Chih-Yang HuangGraduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
Fuu-Jen TsaiGraduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
Boris PascheDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Kounosuke WatabeDepartment of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Hui-Kuan LinDepartment 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; Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address: hulin@wakehealth.edu.
Wake Forest University · USThe University of Texas MD Anderson Cancer Center · USChina Medical University · TWAsia University · TWNational Health Research Institutes · TW
Funding
Tumor Tissue CoreP30CA012197 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI Ruben A. Mesa · 1985 to 2026
$55.4MRole of PUFA-Gene Interactions in Health DisparitiesR01AT008621 · NCCIH · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI FLOYD H CHILTON, Susan Schembre · 2016 to 2026
$5.4MThe Role of Hepatocyte ABCA1 in Lipid Mobilization and TransportR01HL119962 · NHLBI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI PARKS, JOHN S · 2013 to 2022
$3.9MRoles of hyaluronic acid in cancer stem cell nicheR01CA173499 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI WATABE, KOUNOSUKE · 2014 to 2018
$2.3MRoles of long-non-coding RNA, XIST, in brain metastasis of breast cancerR01CA205067 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI WATABE, KOUNOSUKE · 2017 to 2021
$2.2MRole of inflammation and microRNA network in brain metastasis of breast cancerR01CA185650 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI WATABE, KOUNOSUKE · 2016 to 2020
$1.9MIdentification of a new strategy for cancer therapyR01CA193813 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI LIN, HUI-KUAN · 2015 to 2019
$1.8MNovel posttranslational modification in LKB1 activation and cancer developmentR01CA182424 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI LIN, HUI-KUAN · 2014 to 2018
$1.6MThe crosstalk between the PI3K/Akt signal and Skp2 in prostate cancer progressionR01CA136787 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI LIN, HUI-KUAN · 2010 to 2014
$1.6MTranslational Oncology Training ProgramT32CA247819 · NCI · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI PARDEE, TIMOTHY SEBASTIAN, WATABE, KOUNOSUKE · 2020 to 2024
$1.4MNCCIH NIH HHS R01 AT008621NCI NIH HHS P30 CA012197NCI NIH HHS R01 CA136787NCI NIH HHS R01 CA173499NCI NIH HHS R01 CA182424NCI NIH HHS R01 CA185650NCI NIH HHS R01 CA193813NCI NIH HHS R01 CA205067NCI NIH HHS T32 CA247819NHLBI NIH HHS R01 HL119962
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.
Indexed as
Citric Acid CycleAMP-Activated Protein KinasesAnimalsBreast NeoplasmsCatalytic DomainCell Line, TumorCell SurvivalEnzyme ActivationFemaleHumansMice, Inbred BALB CMice, NudeNeoplasm MetastasisPhosphorylationPhosphoserinePyruvate Dehydrogenase ComplexAMP-Activated Protein KinasesPhosphoserinePyruvate Dehydrogenase ComplexAMPKbreast cancercancer metastasismetabolic stressPDHATCA cycle
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