Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation

Nature Communications
Yapeng JiXiaofeng Zheng

Abstract

Targeting the specific metabolic phenotypes of colorectal cancer stem cells (CRCSCs) is an innovative therapeutic strategy for colorectal cancer (CRC) patients with poor prognosis and relapse. However, the context-dependent metabolic traits of CRCSCs remain poorly elucidated. Here we report that adenylate kinase hCINAP is overexpressed in CRC tissues. Depletion of hCINAP inhibits invasion, self-renewal, tumorigenesis and chemoresistance of CRCSCs with a loss of mesenchymal signature. Mechanistically, hCINAP binds to the C-terminal domain of LDHA, the key regulator of glycolysis, and depends on its adenylate kinase activity to promote LDHA phosphorylation at tyrosine 10, resulting in the hyperactive Warburg effect and the lower cellular ROS level and conferring metabolic advantage to CRCSC invasion. Moreover, hCINAP expression is positively correlated with the level of Y10-phosphorylated LDHA in CRC patients. This study identifies hCINAP as a potent modulator of metabolic reprogramming in CRCSCs and a promising drug target for CRC invasion and metastasis.

References

Sep 1, 1980·European Journal of Biochemistry·D PomponF Lederer
Jun 24, 1997·Proceedings of the National Academy of Sciences of the United States of America·H ShimC V Dang
Feb 24, 1956·Science·O WARBURG
Sep 10, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Anatoly A StarkovM Flint Beal
Jan 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hui RenXiao-Dong Su
Nov 17, 2005·Molecular and Cellular Biology·Sander GrannemanSusan J Baserga
Nov 24, 2006·Nature·Lucia Ricci-VitianiRuggero De Maria
Jan 27, 2007·Blood·Karin FischerMarina Kreutz
Mar 14, 2007·Molecular Cell·Venugopal BhaskaraTanya T Paull
Jun 6, 2007·Proceedings of the National Academy of Sciences of the United States of America·Piero DalerbaMichael F Clarke
Nov 30, 2007·Nature Reviews. Cancer·Chi V DangJason Yustein
Apr 25, 2008·Nature Reviews. Cancer·Alexandra Klaus, Walter Birchmeier
Sep 12, 2008·Nature Reviews. Cancer·Jane E Visvader, Geoffrey J Lindeman
Nov 7, 2008·Histochemistry and Cell Biology·Girieca Lorusso, Curzio Rüegg
May 23, 2009·Science·Matthew G Vander HeidenCraig B Thompson
May 27, 2009·International Journal of Molecular Sciences·Petras Dzeja, Andre Terzic
Dec 1, 2009·Cell·Jean Paul ThieryM Angela Nieto
Dec 23, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Katrin DietlMarina P Kreutz
Feb 27, 2010·Cellular and Molecular Life Sciences : CMLS·Jinfang ZhangXiaofeng Zheng
Sep 30, 2010·The Journal of Biological Chemistry·Alison BurkartSilvia Corvera
Dec 3, 2010·Nature·Sushma GurumurthyNabeel Bardeesy
Jan 18, 2011·Cancer Immunology, Immunotherapy : CII·Katrin SingerAndreas Mackensen
Feb 15, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ryan D MichalekJeffrey C Rathmell
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Jun 18, 2011·Science·Jonathan S OakhillBruce E Kemp
Sep 9, 2011·Proceedings of the National Academy of Sciences of the United States of America·Erina VlashiFrank Pajonk
Nov 16, 2011·Cancer Research·Franziska HirschhaeuserWolfgang Mueller-Klieser
Dec 14, 2011·IUBMB Life·Andrew P Halestrap, Marieangela C Wilson
Jan 13, 2012·Nature Reviews. Cancer·Long V NguyenConnie J Eaves
Aug 18, 2012·Genes & Development·Michalina JaniszewskaIvan Stamenkovic
Jan 25, 2013·Nature Reviews. Cancer·Bram De Craene, Geert Berx
Jan 26, 2013·Current Opinion in Cell Biology·Jane D HollandWalter Birchmeier
Mar 19, 2013·Cancer Letters·Jeffrey T Chang, Sendurai A Mani
Mar 23, 2013·Cancer Cell·Michael S Schieber, Navdeep S Chandel
Apr 4, 2013·Cell Cycle·Javier A MenendezAlejandro Vazquez-Martin
May 30, 2013·Development·Ng Shyh-ChangLewis C Cantley

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Citations

Jun 9, 2020·Frontiers in Oncology·Aleksandr KlepininPetras Dzeja
Nov 30, 2019·Stem Cells International·Rayana L Bighetti-TrevisanLuciana O Almeida
Oct 20, 2020·Frontiers of Medicine·Deyu ZhangQinong Ye
Dec 8, 2020·Oxidative Medicine and Cellular Longevity·Yang LiuYanfeng Wang
Aug 25, 2020·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Yong ZhangRensheng Wang
Jun 3, 2021·Genes & Development·Jiexi LiRonald A DePinho

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