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Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin.
Gui, Dan Y; Sullivan, Lucas B; Luengo, Alba; Hosios, Aaron M; Bush, Lauren N; Gitego, Nadege; Davidson, Shawn M; Freinkman, Elizaveta; Thomas, Craig J; Vander Heiden, Matthew G.
Afiliación
  • Gui DY; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Sullivan LB; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Luengo A; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Hosios AM; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Bush LN; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Gitego N; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Davidson SM; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Freinkman E; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Thomas CJ; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
  • Vander Heiden MG; The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: mvh@mit.edu.
Cell Metab ; 24(5): 716-727, 2016 11 08.
Article en En | MEDLINE | ID: mdl-27746050
Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis. However, complex I is only one of many inputs that determines the cellular NAD+/NADH ratio, and dependency on complex I is dictated by the activity of other pathways that affect NAD+ regeneration and aspartate levels. This suggests that cancer drug sensitivity and resistance are not intrinsic properties of cancer cells, and demonstrates that the environment can dictate sensitivity to therapies that impact cell metabolism.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácido Aspártico / Complejo I de Transporte de Electrón / Microambiente Tumoral / Metformina / Mitocondrias / NAD / Neoplasias Tipo de estudio: Diagnostic_studies Límite: Animals / Humans Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácido Aspártico / Complejo I de Transporte de Electrón / Microambiente Tumoral / Metformina / Mitocondrias / NAD / Neoplasias Tipo de estudio: Diagnostic_studies Límite: Animals / Humans Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos