| 19874425 |
Rattan R, Giri S, Hartmann L, Shridhar V: Metformin attenuates ovarian cancer cell growth in an AMP- kinase dispensable manner. J Cell Mol Med. 2009 Oct 29.
ABSTRACT Metformin, the most widely used drug for type 2 diabetes activates AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Here, we report that ovarian cell lines VOSE, A2780, CP70, C200, OV202, OVCAR3, SKOV3ip, PE01 and PE04 predominantly express -alpha1, -beta1, -gamma1 and -gamma2 isoforms of AMPK subunits. 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 AMPKalpha and its downstream substrate; ACC (Acetyl Co-carboxylase) and enhanced beta- oxidation of fatty acid, (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 LKB1 (Liver kinase B1) as it failed to activate AMPK-ACC pathway and cell cycle arrest in LKB1 null mouse embryo fibroblasts (mefs). This observation was further supported by using siRNA approach to downregulate LKB1 in ovarian cancer cells. In contrast, metformin inhibited cell proliferation in both wild type and AMPKalpha1/2 null mefs as well as in AMPK silenced ovarian cancer cells. 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 independent pathways. |
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