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Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells
Mahvash Zakikhani1, Ryan Dowling, I George Fantus
1Department of Oncology, McGill University, Montreal, Quebec, Canada.
Abstract:
Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment.
Insights
Metformin, a diabetes drug, inhibits epithelial cell growth by activating AMP kinase pathway. This mechanism may explain metformin's potential anti-cancer effects, suggesting new therapeutic avenues.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Metformin is a common type 2 diabetes medication known to lower blood glucose and reduce hyperinsulinemia.
- Insulin and insulin-like growth factors can stimulate the proliferation of normal and cancerous cells.
- Population studies suggest metformin use may correlate with reduced cancer incidence and improved prognosis.
Purpose of the Study:
- To investigate the effect of metformin on epithelial cell growth.
- To determine if metformin acts as a growth inhibitor or insulin sensitizer for epithelial cells.
- To elucidate the molecular mechanisms underlying metformin's effects on cell proliferation.
Main Methods:
- Investigated metformin's effect on epithelial cell growth in vitro.
- Utilized small interfering RNA (siRNA) against AMP kinase to assess its role in metformin's effects.
- Measured activation of mammalian target of rapamycin (mTOR) and S6 kinase pathways.
- Assessed global mRNA translation rates.
Main Results:
- Metformin demonstrated a growth inhibitory effect on epithelial cells, contrary to an insulin-sensitizing role.
- AMP kinase pathway activation was essential for metformin-induced growth inhibition, as confirmed by siRNA experiments.
- Metformin treatment led to decreased activation of mTOR and S6 kinase.
- A general reduction in mRNA translation was observed in metformin-treated cells.
Conclusions:
- Metformin inhibits epithelial cell growth via activation of the AMP kinase pathway.
- This mechanism provides a potential explanation for the observed antineoplastic effects of metformin in population studies.
- Further research into AMP kinase activators for cancer prevention and treatment is warranted.
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