title: 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: Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, Maryland, USA.
authors: Wing-Hang
authors: WH
authors: Tong
authors: Carole
authors: C
authors: Sourbier
authors: Gennady
authors: G
authors: Kovtunovych
authors: Suh Young
authors: SY
authors: Jeong
authors: Manish
authors: M
authors: Vira
authors: Manik
authors: M
authors: Ghosh
authors: Vladimir Valera
authors: VV
authors: Romero
authors: Rachid
authors: R
authors: Sougrat
authors: Sophie
authors: S
authors: Vaulont
authors: Benoit
authors: B
authors: Viollet
authors: Yeong-Sang
authors: YS
authors: Kim
authors: Sunmin
authors: S
authors: Lee
authors: Jane
authors: J
authors: Trepel
authors: Ramaprasad
authors: R
authors: Srinivasan
authors: Gennady
authors: G
authors: Bratslavsky
authors: Youfeng
authors: Y
authors: Yang
authors: W Marston
authors: WM
authors: Linehan
authors: Tracey A
authors: TA
authors: Rouault
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000096:biosynthesis; D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D027682:Cation Transport Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D000090463:Iron Deficiencies; D035941:Iron Regulatory Protein 1 / Q000096:biosynthesis / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000096:biosynthesis / Q000378:metabolism; D007680:Kidney Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018231:Leiomyomatosis / Q000151:congenital* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009249:NADP / Q000096:biosynthesis; D009386:Neoplastic Syndromes, Hereditary; D012266:Ribose / Q000096:biosynthesis; D038601:Ribosomal Protein S6 / Q000096:biosynthesis / Q000378:metabolism; D012878:Skin Neoplasms; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014594:Uterine Neoplasms; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D055372:AMP-Activated Protein Kinases; D000105:Acetyl Coenzyme A; D000103:Acetyl-CoA Carboxylase; D051792:Basic Helix-Loop-Helix Proteins; D027682:Cation Transport Proteins; D005649:Fumarate Hydratase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D009249:NADP; D012266:Ribose; D038601:Ribosomal Protein S6; D013804:Thenoyltrifluoroacetone; D016159:Tumor Suppressor Protein p53; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2; C497443:Hif1a protein, mouse