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

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.
Authors	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
Journal	Cancer cell (Cancer Cell) Vol. 20 Issue 3 Pg. 315-27 (Sep 13 2011) ISSN: 1878-3686 [Electronic] United States
PMID	21907923 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Copyright	Copyright © 2011 Elsevier Inc. All rights reserved.
Chemical References	Basic Helix-Loop-Helix Transcription Factors Cation Transport Proteins Hif1a protein, mouse Hypoxia-Inducible Factor 1, alpha Subunit Ribosomal Protein S6 Tumor Suppressor Protein p53 solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2 endothelial PAS domain-containing protein 1 Thenoyltrifluoroacetone NADP Ribose Acetyl Coenzyme A AMP-Activated Protein Kinases Fumarate Hydratase Iron Regulatory Protein 1 Iron Regulatory Protein 2 Acetyl-CoA Carboxylase
Topics	AMP-Activated Protein Kinases (metabolism) Acetyl Coenzyme A (biosynthesis) Acetyl-CoA Carboxylase (biosynthesis, metabolism) Animals Basic Helix-Loop-Helix Transcription Factors (biosynthesis) Cation Transport Proteins (biosynthesis) Cell Line, Tumor Fumarate Hydratase (deficiency, metabolism) Glycolysis (drug effects) Humans Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics) Iron Deficiencies Iron Regulatory Protein 1 (biosynthesis, metabolism) Iron Regulatory Protein 2 (biosynthesis, metabolism) Kidney Neoplasms (enzymology, metabolism, pathology) Leiomyomatosis (congenital, metabolism, pathology) Mice NADP (biosynthesis) Neoplastic Syndromes, Hereditary Ribose (biosynthesis) Ribosomal Protein S6 (biosynthesis, metabolism) Skin Neoplasms Thenoyltrifluoroacetone (pharmacology) Tumor Suppressor Protein p53 (biosynthesis) Uterine Neoplasms

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