MATE2 Expression Is Associated With Cancer Cell Response to Metformin
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BACKGROUND: There is great interest in repurposing the commonly prescribed anti-diabetic drug metformin for cancer therapy. Intracellular uptake and retention of metformin is affected by the expression of organic cation transporters (OCT) 1-3 and by multidrug and toxic compound extrusion (MATE) 1-2. Inside cells, metformin inhibits mitochondrial function, which leads to reduced oxygen consumption and inhibition of proliferation. Reduced oxygen consumption can lead to improved tumor oxygenation and radiation response. PURPOSE: Here we sought to determine if there is an association between the effects of metformin on inhibiting oxygen consumption, proliferation and expression of OCTs and MATEs in a panel of 19 cancer cell lines. RESULTS: There was relatively large variability in the anti-proliferative response of different cell lines to metformin, with a subset of cell lines being very resistant. In contrast, all cell lines demonstrated sensitivity to the inhibition of oxygen consumption by metformin, with relatively small variation. The expression of OCT1 correlated with expression of both OCT2 and OCT3. OCT1 and OCT2 were relatively uniformly expressed, whereas expression of OCT3, MATE1 and MATE2 showed substantial variation across lines. There were statistically significant associations between resistance to inhibition of proliferation and MATE2 expression, as well as between sensitivity to inhibition of oxygen consumption and OCT3 expression. One cell line (LNCaP) with high OCT3 and low MATE2 expression in concert, had substantially higher intracellular metformin concentration than other cell lines, and was exquisitely sensitive to both anti-proliferative and anti-respiratory effects. In all other cell lines, the concentration of metformin required to inhibit oxygen consumption acutely in vitro was substantially higher than that achieved in the plasma of diabetic patients. However, administering anti-diabetic doses of metformin to tumor-bearing mice resulted in intratumoral accumulation of metformin and reduced hypoxic tumor fractions. CONCLUSIONS: All cancer cells are susceptible to inhibition of oxygen consumption by metformin, which results in reduced hypoxic tumor fractions beneficial for the response to radiotherapy. High MATE2 expression may result in resistance to the anti-proliferative effect of metformin and should be considered as a negative predictive biomarker in clinical trials.
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In LnCaP prostate cancer line, very high concentrations up to 10mM of metformin were required to see significant inhibition, and a strong significant correlation between inhibition of proliferation and MATE2 expression was not seen.
“In contrast and although LnCaP, a prostate cancer line, proved to be particularly sensitive to metformin and in a concentration range that was within that expected clinically and correlated with a high expression of mRNA for OCT3 and low expression of MATE2 for the other cell lines, very high concentrations, up to 10mM, of metformin were required to see significant inhibition, and a strong”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [254]
Collectively, these data suggest that expression levels of the uptake and extrusion transporters are not necessarily the limiting factors determining the anti-proliferative effects of metformin and that genetically determined variations in signaling pathways are variably important as are nutrient levels in the tumor microenvironment.
“Collectively, these data suggest that expression levels of the uptake and extrusion transporters are not necessarily the limiting factors determining the anti-proliferative effects of metformin and that genetically determined variations in signaling pathways are variably important as are nutrient levels in the tumor microenvironment (249, 254).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [254]
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Self-citationUnderstanding Cisplatin Pharmacokinetics and Toxicodynamics to Predict and Prevent Kidney Injury
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- Authors
- Chowdhury, S., Yung, E., Pintilie, M., Muaddi, H., Chaib, S., Yeung, M., Fusciello, M., Sykes, J., Pitcher, B., Hagenkort, A., McKee, T., Vellanki, R., Chen, E., Bristow, R. G., Wouters, B. G., & Koritzinsky, M.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Koritzinsky, Marianne
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-12-13
- Volume
- 11
- Issue
- 12
- Pages
- e0165214
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5154501
- OpenAlex
- W2567191481
- Cited by
- 33
- References
- 66
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 1 · 2017: 2
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Princess Margaret Cancer Foundation
- Prostate Cancer Canada
- Terry Fox Research Institute (PPG14-1036)
- Turun Yliopistollinen Keskussairaala
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- metformin, organic cation transporters, OCT3, tumor cell proliferation, oxygen consumption, tumor hypoxia, drug resistance, intracellular drug accumulation, radiation response, predictive biomarkers, cancer cell lines
- MeSH terms
- Animals, Antineoplastic Agents, Cells, Cultured, HeLa Cells, Humans, Hypoglycemic Agents, Metformin, Neoplasms, Experimental, Oxygen Consumption, Biomarkers, Tumor, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Organic Cation Transport Proteins, HCT116 Cells, Cell Proliferation, Octamer Transcription Factors, Mice
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