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Cancer Cell. 2011 Sep 13;20(3):315-27. doi: 10.1016/j.ccr.2011.07.018.

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

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  • 1Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, Maryland, USA.

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.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21907923
[PubMed - indexed for MEDLINE]
PMCID:
PMC3174047
Free PMC Article

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