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

Wing Hang Tong, Carole Sourbier, Gennady Kovtunovych, Suh Young Jeong, Manish Vira, Manik Ghosh, Vladimir Valera Romero, Rachid Sougrat, Sophie Vaulont, Benoit Viollet, Yeong Sang Kim, Sunmin Lee, Jane Trepel, Ramaprasad Srinivasan, Gennady Bratslavsky, Youfeng Yang, W. Marston Linehan, Tracey A. Rouault

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)315-327
Number of pages13
JournalCancer Cell
Volume20
Issue number3
DOIs
StatePublished - Sep 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels'. Together they form a unique fingerprint.

Cite this