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The Effects of Adiponectin and Metformin on Prostate and Colon Neoplasia Involve Activation of AMP-Activated Protein Kinase

Authors' Affiliations: ¹ Department of Oncology, ² Department of Biochemistry, and ³ McGill Cancer Center, McGill University; and ⁴ Cancer Prevention Center, Jewish General Hospital, Montreal, Quebec, Canada

Requests for reprints: Michael N. Pollak, Cancer Prevention Center, E-763, Jewish General Hospital, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T 1E2. Phone: 514-340-8222, ext. 4139; Fax: 514-340-8600; E-mail: michael.pollak{at}mcgill.ca.

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 increased risk of aggressive prostate and colon cancer. We show here that adiponectin activates AMP-activated protein kinase (AMPK) in colon (HT-29) and prostate (PC-3) cancer cells. These results are consistent with prior observations in myocytes, but we show that in epithelial cancer cells AMPK activation is associated with reduction in mammalian target of rapamycin activation as estimated by Ser²⁴⁴⁸ phosphorylation, with reduction in p70S6 kinase activation as estimated by Thr³⁸⁹ phosphorylation, with ribosomal protein S6 activation as estimated by Ser^235/236 phosphorylation, with reduction in protein translation as estimated by [³⁵S]methionine incorporation, and with growth inhibition. Adiponectin-induced growth inhibition is significantly attenuated when AMPK level is reduced using small interfering RNA, indicating that AMPK is involved in mediating the antiproliferative action of this adipokine. Thus, adiponectin has the characteristics of a AMPK-dependent growth inhibitor that is deficient in obesity, and this may contribute to the adverse effects of obesity on neoplastic disease. Furthermore, metformin was observed to activate AMPK and to have growth inhibitory actions on prostate and colon cancer cells, suggesting that this compound may be of particular value in attenuating the adverse effects of obesity on neoplasia.

Key Words: prevention • obesity • adiponectin • metformin • proliferation