Adiponectin and metformin inhibit prostate and colon cancer cell proliferation via AMP kinase (AMPK)- dependent mechanisms Free

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Background: Population studies provide evidence that obesity and insulin resistance are associated not only with elevated serum insulin levels and reduced serum adiponectin levels, but also with poor prognosis among prostate and colon cancer patients. There is intense interest in identifying the metabolic mediators linking obesity to aggressive cancer behavior. We recently showed (Cancer Research 66: 10269, 2006) that metformin inhibits mTOR (Ser²⁴⁴⁸ ) phosphorylation and acts as a growth inhibitor for breast cancer cells via an AMPK-dependent mechanism. Prior work (Nature Medicine 8: 1288, 2002) showed that the metabolic effect of adiponectin as a stimulator of muscle glucose uptake involves activation of AMPK. Methods: PC-3 (prostate cancer) and HT29 (colon cancer) cell lines were treated with metformin or adiponectin with or without siRNA against AMPK. Proliferation assays were performed using Alamar reducing dye, and signaling pathway activation was studied by Western blot using phospho-specific antibodies. Results: We demonstrate that adiponectin is a potent growth inhibitor (~50% growth inhibition at 25 ng/ml for PC-3 cells and 500 ng/ml for HT-29 cells) and AMPK activator for colon and prostate cancer cells in vitro. This growth inhibition is associated with reduction of phospho-mTOR (Ser²⁴⁴⁸) and phospho-S6K (Ser^235/236 ) levels, and is significantly attenuated when AMPK level is reduced by siRNA (using a negative control siRNA). We also extend our prior results by showing that metformin inhibits colon and prostate cancer cell growth in vitro via an AMPK-dependent mechanism. Conclusion: Adiponectin activates AMPK in colon and prostate cancer cells, consistent with prior observations in myocytes, but in the epithelial cancer cells an important consequence is growth inhibition associated with reduction in mTOR activation. Thus, the adverse associations of the low adiponectin levels found in obesity and insulin resistance with cancer risk and prognosis may involve at least in part reduced AMPK activation and secondarily increased mTOR signaling in at-risk or transformed epithelial cell populations.