Environment dictates dependence on mitochondrial complex I for NAD+ and aspartate production and determines cancer cell sensitivity to metformin
Open accessAbstract
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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Recent work shows that the anti-tumorigenic effect of metformin can be at least partially accounted for by direct mitochondrial complex I inhibition in tumors.
“Although the precise mechanism of metformin action remains controversial (Luengo et al., 2014), recent work has shown that the anti-tumorigenic effect of metformin can at least be partially accounted for by direct mitochondrial complex I inhibition in tumors (Gui et al., 2016; Wheaton et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Gui et al., 2016
Proliferating cells often require a high NAD+/NADH ratio to support anabolic reactions, and in some contexts the NAD+/NADH ratio directly correlates with proliferation rate.
“Proliferating cells often require a high NAD+/NADH ratio to support anabolic reactions, and in some contexts the NAD+/NADH ratio directly correlates with proliferation rate (Gui et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Gui et al., 2016
Cancer tissue-of-origin has served as a successful way to select patients for chemotherapies targeting metabolism for decades, and environment can influence the efficacy of drugs targeting DHODH, mitochondrial complex I, and glutaminase.
“Cancer tissue-of-origin has served as a successful way to select patients for chemotherapies targeting metabolism for decades, and environment can also influence the efficacy of drugs targeting DHODH, mitochondrial complex I, and glutaminase (Davidson et al., 2016; Gui et al., 2016; Marin-Valencia et al., 2012; Sellers et al., 2015; Sykes et al., 2016; Tardito et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Gui et al., 2016
Altering culture media conditions is sufficient to change cancer cell sensitivity to metformin, highlighting the importance of environment in modulating metabolic dependencies.
“Altering culture media conditions is sufficient to change cancer cell sensitivity to metformin, highlighting the importance of environment in modulating metabolic dependencies.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Gui et al., 2016
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- Authors
- Gui, D. Y., Sullivan, L. B., Luengo, A., Hosios, A. M., Bush, L. N., Gitego, N., Davidson, S. M., Freinkman, E., Thomas, C. J., & Vander Heiden, M. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Whitehead Institute for Biomedical Research (US)
- National Institutes of Health (US)
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 24
- Issue
- 5
- Pages
- 716-727
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5102768
- OpenAlex
- W2530859476
- Cited by
- 323
- References
- 55
- Citations by year
- 2026: 15 · 2025: 25 · 2024: 30 · 2023: 28 · 2022: 40 · 2021: 41 · 2020: 51 · 2019: 37 · 2018: 33 · 2017: 22
- FWCI
- 15.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA168653, R01CA201276, P30CA014051)
- National Institute of General Medical Sciences (T32GM007753)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- metformin, mitochondrial complex I, NAD+ regeneration, aspartate biosynthesis, tumor cell proliferation, cancer drug sensitivity, tumor microenvironment, complex I inhibitors, cancer metabolism
- MeSH terms
- Animals, Aspartic Acid, Homeostasis, Humans, Metformin, Mice, Nude, Mitochondria, NAD, Neoplasms, Pyruvic Acid, Electron Transport Complex I, Cell Line, Tumor, Cell Proliferation, Tumor Microenvironment
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