title: Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin.
abstract: 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.
authors.affiliation: The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Dan Y
authors.initials: DY
authors.lastname: Gui
authors.affiliation: The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Lucas B
authors.initials: LB
authors.lastname: Sullivan
authors.affiliation: The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Alba
authors.initials: A
authors.lastname: Luengo
authors.affiliation: The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Hosios
authors.affiliation: The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Bush
authors.affiliation: The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Nadege
authors.initials: N
authors.lastname: Gitego
authors.affiliation: The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Freinkman
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042967:Electron Transport Complex I / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D009369:Neoplasms / Q000473:pathology*; D019289:Pyruvic Acid / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D009243:NAD; D001224:Aspartic Acid; D019289:Pyruvic Acid; D008687:Metformin; D042967:Electron Transport Complex I
keywords: NAD+/NADH ratio; aspartate; biguanide; cancer metabolism; complex I; drug sensitivity; metformin; mitochondria