Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides
Open accessAbstract
As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.
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Earlier work that blocked glycolysis or oxidative phosphorylation found increased activity of the other pathway.
“These findings confirm previous studies that analyzed inhibition of either glycolysis or OXPHOS, and observed an increase in the activity of the other pathway (Hao et al., 2010; Jose et al., 2011; Birsoy et al., 2014; Dykens et al., 2008).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Birsoy et al., 2014
Cancer cells with reduced OXPHOS due to either mutated mitochondrial DNA or impaired glucose utilization were unable to initiate this adaptive response, and were thus particularly sensitive to glucose deprivation to one-tenth of normal levels.
“Cancer cells with reduced OXPHOS due to either mutated mitochondrial DNA or impaired glucose utilization were unable to initiate this adaptive response, and were thus particularly sensitive to glucose deprivation to one-tenth of normal levels (Birsoy et al., 2014).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Birsoy et al., 2014
Previous studies reported synergism of the metformin/low glucose combination.
“These results are consistent with previous studies reporting the synergism of the metformin/low glucose combination (Birsoy et al., 2014; Zhuang et al., 2014).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Birsoy et al., 2014
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- Authors
- Birsoy, K., Possemato, R., Lorbeer, F. K., Bayraktar, E. C., Thiru, P., Yucel, B., Wang, T., Chen, W. W., Clish, C. B., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Sabatini, David M.
- ORCID
- Venue
- Nature
- Published
- 2014-03-16
- Volume
- 508
- Issue
- 7494
- Pages
- 108-112
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4012432
- OpenAlex
- W2104696999
- Cited by
- 710
- References
- 27
- Citations by year
- 2026: 17 · 2025: 44 · 2024: 58 · 2023: 46 · 2022: 60 · 2021: 75 · 2020: 83 · 2019: 71 · 2018: 51 · 2017: 49 · 2016: 61 · 2015: 59 · 2014: 35
- FWCI
- 21.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (CA129105, K99CA168940, CA103866, R01CA103866, R01CA129105, R00CA168940)
- National Institute of General Medical Sciences (T32GM007287)
- National Institute of Allergy and Infectious Diseases (AI-07389, T32AI007389)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- glucose limitation, biguanides, mitochondrial oxidative phosphorylation, cancer metabolism, mitochondrial DNA mutations, complex I, antidiabetic drugs, OXPHOS inhibitors, continuous flow culture, tumor microenvironment, NDI1, glucose utilization, cancer cell lines, drug sensitivity biomarkers
- MeSH terms
- Adenosine Triphosphate, Animals, Biguanides, Culture Media, DNA, Mitochondrial, Glucose, Humans, Hypoglycemic Agents, Male, Mitochondria, Mutation, Neoplasm Transplantation, Neoplasms, Oxidative Phosphorylation, Phenformin, Cell Culture Techniques, Xenograft Model Antitumor Assays, Saccharomyces cerevisiae Proteins, RNA Interference, Electron Transport Complex I, Cell Line, Tumor, Cell Proliferation, Mice, Molecular Typing
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