The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels

Handle URI:
http://hdl.handle.net/10754/561857
Title:
The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels
Authors:
Tong, Winghang; Sourbier, Carole; Kovtunovych, Gennadiy; Jeong, Suhyoung; Vira, Manish A.; Ghosh, Manik Chandra; Romero, Vladimir Valera; Sougrat, Rachid; Vaulont, Sophie; Viollet, Benoît; Kim, Yeongsang; Lee, Sunmin; Trepel, Jane B.; Srinivasan, Ramaprasad; Bratslavsky, Gennady; Yang, Youfeng; Linehan, William Marston; Rouault, Tracey A.
Abstract:
Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells. © 2011 Elsevier Inc.
KAUST Department:
Core Labs
Publisher:
Elsevier BV
Journal:
Cancer Cell
Issue Date:
Sep-2011
DOI:
10.1016/j.ccr.2011.07.018
PubMed ID:
21907923
PubMed Central ID:
PMC3174047
Type:
Article
ISSN:
15356108
Sponsors:
The authors thank our colleagues and thank the intramural programs of the National Institute of Child Health and Human Development and the National Cancer Institute for support.
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174047
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorTong, Winghangen
dc.contributor.authorSourbier, Caroleen
dc.contributor.authorKovtunovych, Gennadiyen
dc.contributor.authorJeong, Suhyoungen
dc.contributor.authorVira, Manish A.en
dc.contributor.authorGhosh, Manik Chandraen
dc.contributor.authorRomero, Vladimir Valeraen
dc.contributor.authorSougrat, Rachiden
dc.contributor.authorVaulont, Sophieen
dc.contributor.authorViollet, Benoîten
dc.contributor.authorKim, Yeongsangen
dc.contributor.authorLee, Sunminen
dc.contributor.authorTrepel, Jane B.en
dc.contributor.authorSrinivasan, Ramaprasaden
dc.contributor.authorBratslavsky, Gennadyen
dc.contributor.authorYang, Youfengen
dc.contributor.authorLinehan, William Marstonen
dc.contributor.authorRouault, Tracey A.en
dc.date.accessioned2015-08-03T09:32:37Zen
dc.date.available2015-08-03T09:32:37Zen
dc.date.issued2011-09en
dc.identifier.issn15356108en
dc.identifier.pmid21907923en
dc.identifier.doi10.1016/j.ccr.2011.07.018en
dc.identifier.urihttp://hdl.handle.net/10754/561857en
dc.description.abstractInactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells. © 2011 Elsevier Inc.en
dc.description.sponsorshipThe authors thank our colleagues and thank the intramural programs of the National Institute of Child Health and Human Development and the National Cancer Institute for support.en
dc.publisherElsevier BVen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174047en
dc.titleThe glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levelsen
dc.typeArticleen
dc.contributor.departmentCore Labsen
dc.identifier.journalCancer Cellen
dc.identifier.pmcidPMC3174047en
dc.contributor.institutionMolecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, MD, United Statesen
dc.contributor.institutionUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United Statesen
dc.contributor.institutionAlbert Einstein College of Medicine, New York, United Statesen
dc.contributor.institutionInstitut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, Franceen
dc.contributor.institutionInserm U 1016, Paris, Franceen
dc.contributor.institutionMedical Oncology Branch, National Cancer Institute, Bethesda, MD, United Statesen
kaust.authorSougrat, Rachiden

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