Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner.
Bottom Line: Our studies show that metformin treatment (1) significantly inhibited proliferation of diverse chemo-responsive and -resistant ovarian cancer cell lines (A2780, CP70, C200, OV202, OVCAR3, SKVO3ip, PE01 and PE04), (2) caused cell cycle arrest accompanied by decreased cyclin D1 and increased p21 protein expression, (3) activated AMPK in various ovarian cancer cell lines as evident from increased phosphorylation of AMPKα and its downstream substrate; acetyl co-carboxylase (ACC) and enhanced β-oxidation of fatty acid and (4) attenuated mTOR-S6RP phosphorylation, inhibited protein translational and lipid biosynthetic pathways, thus implicating metformin as a growth inhibitor of ovarian cancer cells.We also show that metformin-mediated effect on AMPK is dependent on liver kinase B1 (LKB1) as it failed to activate AMPK-ACC pathway and cell cycle arrest in LKB1 mouse embryo fibroblasts (mefs).Collectively, these results provide evidence on the role of metformin as an anti-proliferative therapeutic that can act through both AMPK-dependent as well as AMPK-independent pathways.
Affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.Show MeSH
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Mentions: AMPK also regulates lipid biosynthesis by phosphorylating and inhibiting activity of ACC and HMG CoA reductase, rate-limiting enzymes for fatty acid and cholesterol biosynthesis, respectively [25, 26]. To examine the effect of metformin on lipid biosynthesis, various ovarian cancer cells were treated with metformin (5–20 mM) for 8 hrs followed by [14C] acetate treatment for additional 4 hrs. Metformin treatment significantly inhibited the biosynthesis of both polar (phospholipids) and non-polar (cholesterol and triglycerides) lipids in ovarian cancer cell lines (Fig. 6). Collectively, these results suggest that metformin treatment leads to decreased protein translation and lipid biosynthesis, which may result in limited availability of essential cellular building blocks to the tumour cells, essential for cell growth/survival.
Affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.