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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Acetyl Coenzyme A / biosynthesis
  • Acetyl-CoA Carboxylase / biosynthesis
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Cation Transport Proteins / biosynthesis
  • Cell Line, Tumor
  • Fumarate Hydratase / deficiency*
  • Fumarate Hydratase / metabolism
  • Glycolysis / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Iron / deficiency*
  • Iron Regulatory Protein 1 / biosynthesis
  • Iron Regulatory Protein 1 / metabolism
  • Iron Regulatory Protein 2 / biosynthesis
  • Iron Regulatory Protein 2 / metabolism
  • Kidney Neoplasms / enzymology
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Leiomyomatosis / congenital*
  • Leiomyomatosis / metabolism
  • Leiomyomatosis / pathology
  • Mice
  • NADP / biosynthesis
  • Neoplastic Syndromes, Hereditary
  • Ribose / biosynthesis
  • Ribosomal Protein S6 / biosynthesis
  • Ribosomal Protein S6 / metabolism
  • Skin Neoplasms
  • Thenoyltrifluoroacetone / pharmacology
  • Tumor Suppressor Protein p53 / biosynthesis
  • Uterine Neoplasms

Substances

  • 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
  • Iron
  • AMP-Activated Protein Kinases
  • Fumarate Hydratase
  • Iron Regulatory Protein 1
  • Iron Regulatory Protein 2
  • Acetyl-CoA Carboxylase

Supplementary concepts

  • Hereditary leiomyomatosis and renal cell cancer