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

Zhen Cai; Chien Feng Li; Fei Han; Chunfang Liu; Anmei Zhang; Che Chia Hsu; Danni Peng; Xian Zhang; Guoxiang Jin; Abdol Hossein Rezaeian; Guihua Wang; Weina Zhang; Bo Syong Pan; Chi Yun Wang; Yu Hui Wang; Shih Ying Wu; Shun Chin Yang; Fang Chi Hsu; Ralph B. D'Agostino; Christina M. Furdui; Gregory L. Kucera; John S. Parks; Floyd H. Chilton; Chih Yang Huang; Fuu Jen Tsai; Boris Pasche; Kounosuke Watabe; Hui Kuan Lin

doi:10.1016/j.molcel.2020.09.018

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

Zhen Cai, Chien Feng Li, Fei Han, Chunfang Liu, Anmei Zhang, Che Chia Hsu, Danni Peng, Xian Zhang, Guoxiang Jin, Abdol Hossein Rezaeian, Guihua Wang, Weina Zhang, Bo Syong Pan, Chi Yun Wang, Yu Hui Wang, Shih Ying Wu, Shun Chin Yang, Fang Chi Hsu, Ralph B. D'Agostino, Christina M. FurduiGregory L. Kucera, John S. Parks, Floyd H. Chilton, Chih Yang Huang, Fuu Jen Tsai, Boris Pasche, Kounosuke Watabe, Hui Kuan Lin

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

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.

Original language	English (US)
Pages (from-to)	263-278.e7
Journal	Molecular cell
Volume	80
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2020.09.018
State	Published - Oct 15 2020
Externally published	Yes

Keywords

AMPK
PDHA
TCA cycle
breast cancer
cancer metastasis
metabolic stress

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2020.09.018

Cite this

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, R. B., ... Lin, H. K. (2020). Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis. Molecular cell, 80(2), 263-278.e7. https://doi.org/10.1016/j.molcel.2020.09.018

Cai, Z, Li, CF, Han, F, Liu, C, Zhang, A, Hsu, CC, Peng, D, Zhang, X, Jin, G, Rezaeian, AH, Wang, G, Zhang, W, Pan, BS, Wang, CY, Wang, YH, Wu, SY, Yang, SC, Hsu, FC, D'Agostino, RB, Furdui, CM, Kucera, GL, Parks, JS, Chilton, FH, Huang, CY, Tsai, FJ, Pasche, B, Watabe, K & Lin, HK 2020, 'Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis', Molecular cell, vol. 80, no. 2, pp. 263-278.e7. https://doi.org/10.1016/j.molcel.2020.09.018

@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",

}

TY - JOUR

T1 - Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis

AU - Cai, Zhen

AU - Li, Chien Feng

AU - Han, Fei

AU - Liu, Chunfang

AU - Zhang, Anmei

AU - Hsu, Che Chia

AU - Peng, Danni

AU - Zhang, Xian

AU - Jin, Guoxiang

AU - Rezaeian, Abdol Hossein

AU - Wang, Guihua

AU - Zhang, Weina

AU - Pan, Bo Syong

AU - Wang, Chi Yun

AU - Wang, Yu Hui

AU - Wu, Shih Ying

AU - Yang, Shun Chin

AU - Hsu, Fang Chi

AU - D'Agostino, Ralph B.

AU - Furdui, Christina M.

AU - Kucera, Gregory L.

AU - Parks, John S.

AU - Chilton, Floyd H.

AU - Huang, Chih Yang

AU - Tsai, Fuu Jen

AU - Pasche, Boris

AU - Watabe, Kounosuke

AU - Lin, Hui Kuan

N1 - 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 ’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: © 2020 Elsevier Inc.

PY - 2020/10/15

Y1 - 2020/10/15

N2 - 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.

AB - 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.

KW - AMPK

KW - PDHA

KW - TCA cycle

KW - breast cancer

KW - cancer metastasis

KW - metabolic stress

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JF - Molecular Cell

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ER -

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

Abstract

Keywords

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