Abstract 187: Clinically relevant efficacious doses of resveratrol induce changes in the AMPK/mTOR pathway, accompanied with senescence in preclinical models of colorectal cancer .

Abstract

Abstract Resveratrol, a polyphenol present in red wine and peanuts exerts an array of beneficial effects, including anticancer activity and calorie restriction (CR) mimicry. Recent work from our laboratory has shown that low doses of resveratrol, comparable to amounts contained in a glass of red wine significantly reduced adenoma development in ApcMin mice when given with a high fat diet (Scott et al, unpublished). The protective effect was more pronounced than that caused by higher amounts, equivalent to doses used in clinical trials. The CR activity of resveratrol is mediated via the energy regulator AMP-activated kinase (AMPK). This study aims to investigate whether AMPK signalling contributes to the chemopreventive effect of resveratrol. Intestinal mucosa from female ApcMin mice maintained on a high fat diet containing resveratrol (0.00007 or 0.014% in their diet) for 10 weeks was analysed by Western blotting to assess AMPK signalling, and the induction of autophagy and senescence. For more detailed mechanistic interrogation APC10.1 cells originally derived from adenomas of ApcMin mice were incubated with resveratrol (0.001-10μM) for 6 days and protein expression examined. The extent of AMPK activation in vivo correlated with the degree of adenoma inhibition; AMPK expression and phosphorylation was evident in mucosa of resveratrol treated mice, but not in control animals, with highest levels in those that ingested the low dose. This chronic resveratrol treatment was also associated with increased expression of p21, a biomarker of senescence, particularly at the low dose. In APC10.1 cells resveratrol caused significant increases in AMPK phosphorylation at 0.01, 0.1 and 1μM, but not at 10μM, consistent with a bell-shaped dose-response. Activity was accompanied by significantly reduced phosphorylation of the mammalian target of rapamycin (mTOR), which is regulated by AMPK signalling, plus its downstream targets p70S6K and 4E-BP1. Furthermore, these concentrations also increased autophagy and senescence, as measured by LC3-II and p21 expression, respectively, and greater numbers of senescence-associated β-galactosidase positive cells. The results suggest that activation of AMPK signalling and the induction of senescence may contribute to the cancer chemopreventive effects of resveratrol at dietary relevant intakes. Citation Format: Abeer O. Kholghi. Clinically relevant efficacious doses of resveratrol induce changes in the AMPK/mTOR pathway, accompanied with senescence in preclinical models of colorectal cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 187. doi:10.1158/1538-7445.AM2013-187