@article{933b5f7c07124579b2ea5c8dcec5fe8f,
title = "Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis",
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.",
keywords = "AMPK, PDHA, TCA cycle, breast cancer, cancer metastasis, metabolic stress",
author = "Zhen Cai and Li, {Chien Feng} and Fei Han and Chunfang Liu and Anmei Zhang and Hsu, {Che Chia} and Danni Peng and Xian Zhang and Guoxiang Jin and Rezaeian, {Abdol Hossein} and Guihua Wang and Weina Zhang and Pan, {Bo Syong} and Wang, {Chi Yun} and Wang, {Yu Hui} and Wu, {Shih Ying} and Yang, {Shun Chin} and Hsu, {Fang Chi} and D'Agostino, {Ralph B.} and Furdui, {Christina M.} and Kucera, {Gregory L.} and Parks, {John S.} and Chilton, {Floyd H.} and Huang, {Chih Yang} and Tsai, {Fuu Jen} and Boris Pasche and Kounosuke Watabe and Lin, {Hui Kuan}",
note = "Funding Information: We thank Drs. Z. Lu and Amit Maity for providing reagents. We acknowledge the support of Wake Forest Baptist Comprehensive Cancer Center Cell & Flow Cytometry Shared Resource, supported by the National Cancer Institute's Cancer Center Support Grant (P30CA012197), United States. This work was supported by start-up funds from Wake Forest School of Medicine, endowed funds from Anderson Discovery Professor for Cancer Research, NIH grants (R01CA136787, R01CA182424, and R01CA193813), PPG developmental grant from Wake Forest Cancer Center, United States (to H.-K.L.), Breast Cancer Pilot Award from Wake Forest Cancer Center, United States (to Z.C.), and Health and welfare surcharge of tobacco products (MOHW109-TDU-B-212-134014), Taiwan (to C.-F.L.). Z.C. and H.-K.L. designed the experiments. Z.C. C.-F.L. X.Z. C.-C.H. A.-H.R. D.P. G.J. F.H. C.-Y.W. A.Z. S.-Y.W. and B.-S.P. performed the experiments. F.-C.H. and R.B.D. performed statistical analysis. Y.-H.W. S.-C.Y. G.W. W.Z. C.M.F. G.L.K. J.S.P. F.H.C. C.-Y.H. F.-J.T. B.P. and K.W. provided technical support, scientific insights, and suggestions. Z.C. D.P. and H.-K.L. wrote the manuscript. All authors discussed and read the manuscript. The authors declare no competing interests. Funding Information: We thank Drs. Z. Lu and Amit Maity for providing reagents. We acknowledge the support of Wake Forest Baptist Comprehensive Cancer Center Cell & Flow Cytometry Shared Resource , supported by the National Cancer Institute {\textquoteright}s Cancer Center Support Grant ( P30CA012197 ), United States. This work was supported by start-up funds from Wake Forest School of Medicine , endowed funds from Anderson Discovery Professor for Cancer Research , NIH grants ( R01CA136787 , R01CA182424 , and R01CA193813 ), PPG developmental grant from Wake Forest Cancer Center , United States (to H.-K.L.), Breast Cancer Pilot Award from Wake Forest Cancer Center , United States (to Z.C.), and Health and welfare surcharge of tobacco products ( MOHW109-TDU-B-212-134014 ), Taiwan (to C.-F.L.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = oct,
day = "15",
doi = "10.1016/j.molcel.2020.09.018",
language = "English (US)",
volume = "80",
pages = "263--278.e7",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}