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
Related in: MedlinePlus
Mentions: To determine if metformin-mediated inhibition of cell proliferation may reflect changes in cell cycle, we examined cell cycle distribution by flow cytometry. As depicted in Fig. 3A, metformin treatment led to accumulation of cells in G1-phase with corresponding decrease in the percentage of cells in the S-phase in all ovarian cancer cell lines tested compared to untreated cells. Consistent with this G1 arrest, immunoblot analysis revealed that metformin treatment resulted in reduced cyclin D1 levels with concomitant increase in the expression of p21 in A2780, CP70, C200 and SKOV3ip cells; however, there was no change in the expression of p27 (Fig. 3B). Densitometric representation of the data is shown in Fig. S2. Collectively, these results suggest that metformin inhibits cell cycle progression by modulating the expression of cell cycle proteins.
Affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.