Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells.

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  • Author(s): Filipp FV;Filipp FV; Scott DA; Ronai ZA; Osterman AL; Smith JW
  • Source:
    Pigment cell & melanoma research [Pigment Cell Melanoma Res] 2012 May; Vol. 25 (3), pp. 375-83. Date of Electronic Publication: 2012 Mar 27.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Blackwell Munksgaard Country of Publication: England NLM ID: 101318927 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1755-148X (Electronic) Linking ISSN: 17551471 NLM ISO Abbreviation: Pigment Cell Melanoma Res Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford : Blackwell Munksgaard,
    • Subject Terms:
      Citric Acid Cycle/*physiology ; Hypoxia/*metabolism ; Isocitrate Dehydrogenase/*physiology ; Lipogenesis/*physiology ; Melanoma/*metabolism ; Skin Neoplasms/*metabolism; Cell Line, Tumor ; Citric Acid Cycle/drug effects ; Citric Acid Cycle/genetics ; Gene Expression Regulation, Enzymologic/drug effects ; Gene Knockdown Techniques ; Humans ; Hypoxia/complications ; Hypoxia/genetics ; Hypoxia/pathology ; Isocitrate Dehydrogenase/genetics ; Isocitrate Dehydrogenase/metabolism ; Lipogenesis/drug effects ; Lipogenesis/genetics ; Melanoma/complications ; Melanoma/genetics ; Melanoma/pathology ; Metabolic Networks and Pathways/drug effects ; Metabolic Networks and Pathways/genetics ; Metabolic Networks and Pathways/physiology ; Models, Biological ; RNA, Small Interfering/pharmacology ; Skin Neoplasms/complications ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology
    • Abstract:
      The tricarboxylic acid (TCA) cycle is the central hub of oxidative metabolism, running in the classic forward direction to provide carbon for biosynthesis and reducing agents for generation of ATP. Our metabolic tracer studies in melanoma cells showed that in hypoxic conditions the TCA cycle is largely disconnected from glycolysis. By studying the TCA branch point metabolites, acetyl CoA and citrate, as well as the metabolic endpoint glutamine and fatty acids, we developed a comprehensive picture of the rewiring of the TCA cycle that occurs in hypoxia. Hypoxic tumor cells maintain proliferation by running the TCA cycle in reverse. The source of carbon for acetyl CoA, citrate, and fatty acids switches from glucose in normoxia to glutamine in hypoxia. This hypoxic flux from glutamine into fatty acids is mediated by reductive carboxylation. This reductive carboxylation is catalyzed by two isocitrate dehydrogenases, IDH1 and IDH2. Their combined action is necessary and sufficient to effect the reverse TCA flux and maintain cellular viability.
      (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)
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    • Grant Information:
      CA-154887 United States CA NCI NIH HHS; K99 CA154887 United States CA NCI NIH HHS; CA-140427 United States CA NCI NIH HHS; R00 CA154887 United States CA NCI NIH HHS; K99 CA154887-02 United States CA NCI NIH HHS; P01 CA128814 United States CA NCI NIH HHS; K99 CA154887-01 United States CA NCI NIH HHS; CA-128814 United States CA NCI NIH HHS
    • Accession Number:
      0 (RNA, Small Interfering)
      EC 1.1.1.41 (IDH2 protein, human)
      EC 1.1.1.41 (Isocitrate Dehydrogenase)
      EC 1.1.1.42. (IDH1 protein, human)
    • Publication Date:
      Date Created: 20120225 Date Completed: 20120827 Latest Revision: 20220812
    • Publication Date:
      20240829
    • Accession Number:
      PMC3329592
    • Accession Number:
      10.1111/j.1755-148X.2012.00989.x
    • Accession Number:
      22360810