Metformin Inhibits the Inflammatory Response Associated With Cellular Transformation and Cancer Stem Cell Growth
Open accessAbstract
Metformin, the first-line drug for treating diabetes, inhibits cellular transformation and selectively kills cancer stem cells in breast cancer cell lines. In a Src-inducible model of cellular transformation, metformin inhibits the earliest known step in the process, activation of the inflammatory transcription factor NF-κB. Metformin strongly delays cellular transformation in a manner similar to that occurring upon a weaker inflammatory stimulus. Conversely, inhibition of transformation does not occur if metformin is added after the initial inflammatory stimulus. The antitransformation effect of metformin can be bypassed by overexpression of Lin28B or IL1β, downstream targets of NF-κB. Metformin preferentially inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in cancer stem cells compared with non-stem cancer cells in the same population. The ability of metformin to block tumor growth and prolong remission in xenografts in combination with doxorubicin is associated with decreased function of the inflammatory feedback loop. Lastly, metformin-based combinatorial therapy is effective in xenografts involving inflammatory prostate and melanoma cell lines, whereas it is ineffective in noninflammatory cell lines from these lineages. Taken together, our observations suggest that metformin inhibits a signal transduction pathway that results in an inflammatory response. As metformin alters energy metabolism in diabetics, we speculate that metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers.
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Several other studies using a variety of cell types have reported that metformin inhibits NF-κB activation, decreases production of inflammatory cytokines and genes that code for inflammatory response, supporting healthspan benefits of metformin.
“Several other studies using a variety of different cell types have reported that metformin inhibits NF-κB activation, decreases the production of inflammatory cytokines and the genes that code for the inflammatory response thus supporting the healthspan benefits of metformin (105, 194–196).”
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 [196]
Metformin has additional benefit for conditions like polycystic ovary syndrome, atherosclerosis, cancer, COVID-19, and obesity.
“Aside from its anti-hyperglycemic effects, metformin has an additional benefit for conditions like polycystic ovary syndrome, atherosclerosis, cancer, coronavirus disease 2019 (COVID-19), and obesity (7–14).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [9]
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- Authors
- Hirsch, H. A., Iliopoulos, D., & Struhl, K.
- Affiliations
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-12-31
- Volume
- 110
- Issue
- 3
- Pages
- 972-977
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3549132
- OpenAlex
- W2154285890
- Cited by
- 440
- References
- 34
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 19 · 2023: 31 · 2022: 22 · 2021: 27 · 2020: 34 · 2019: 35 · 2018: 37 · 2017: 43 · 2016: 43 · 2015: 52 · 2014: 47 · 2013: 28
- FWCI
- 16.31
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA107486, CA107486)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- metformin, cancer stem cells, cell transformation, NF-κB, inflammation, STAT3 phosphorylation, LIN28B, IL-1β, Src kinase, doxorubicin combination therapy, prostate cancer, melanoma, tumor xenografts, metabolic stress response, energy metabolism
- MeSH terms
- Animals, Breast Neoplasms, Cell Line, Cell Transformation, Neoplastic, Doxorubicin, Female, Humans, Hypoglycemic Agents, Inflammation, Metformin, Mice, Nude, Stress, Physiological, Neoplastic Stem Cells, NF-kappa B, Anticarcinogenic Agents, Xenograft Model Antitumor Assays, Feedback, Physiological, Cell Line, Tumor, STAT3 Transcription Factor, Mice
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