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dc.contributor.authorFreinkman, Elizaveta
dc.contributor.authorThomas, Craig J.
dc.contributor.authorGui, Dan Yi
dc.contributor.authorSullivan, Lucas Bryan
dc.contributor.authorLuengo, Alba
dc.contributor.authorHosios, Aaron Marc
dc.contributor.authorBush, Lauren N.
dc.contributor.authorGitego, Nadege
dc.contributor.authorDavidson, Shawn M
dc.contributor.authorVander Heiden, Matthew G.
dc.date.accessioned2018-07-11T20:19:18Z
dc.date.available2018-07-11T20:19:18Z
dc.date.issued2016-10
dc.date.submitted2016-07
dc.identifier.issn1550-4131
dc.identifier.issn1932-7420
dc.identifier.urihttp://hdl.handle.net/1721.1/116918
dc.description.abstractMetformin 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. Keywords: cancer metabolism; metformin; biguanide; NAD+/NADH ratio; drug sensitivity; complex I; mitochondria; aspartateen_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant P30CA1405141)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant GG006413)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant R01 CA168653)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant R01 CA201276)en_US
dc.publisherElsevieren_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/J.CMET.2016.09.006en_US
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs Licenseen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.sourcePMCen_US
dc.titleEnvironment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metforminen_US
dc.typeArticleen_US
dc.identifier.citationGui, Dan Y. et al. “Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin.” Cell Metabolism 24, 5 (November 2016): 716–727 © 2016 Elsevier Incen_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorGui, Dan Yi
dc.contributor.mitauthorSullivan, Lucas Bryan
dc.contributor.mitauthorLuengo, Alba
dc.contributor.mitauthorHosios, Aaron Marc
dc.contributor.mitauthorBush, Lauren N.
dc.contributor.mitauthorGitego, Nadege
dc.contributor.mitauthorDavidson, Shawn M
dc.contributor.mitauthorVander Heiden, Matthew G.
dc.relation.journalCell Metabolismen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2018-07-11T17:49:19Z
dspace.orderedauthorsGui, 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.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0003-0130-3428
dc.identifier.orcidhttps://orcid.org/0000-0002-6745-8222
dc.identifier.orcidhttps://orcid.org/0000-0002-4236-0229
dc.identifier.orcidhttps://orcid.org/0000-0002-7702-5877
dc.identifier.orcidhttps://orcid.org/0000-0002-6702-4192
mit.licensePUBLISHER_CCen_US


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