The majority of the colon tumors overexpress insulin-like growthfactor-1 receptor (IGF-1R) that confers a growth advantage to the cellsin response to endogenous and exogenous IGFs. IGF-1 (elevated during obesity) binding to IGF-1R activates Akt/mTOR signaling pathways implicated in colon cancer cell proliferation. IGF-1R gene expression and phosphorylation are suppressed by p53, a critical tumor suppressor gene. Resveratrol, a stilbenoid derived mainly from the skin of red grapes, activates p53in vitro. However, the inhibitory efficacy of resveratrol against an IGF-1induced colon cell proliferation and the mechanisms of action are not yet fully elucidated. We evaluated the hypothesis that resveratrol suppresses IGF-1 promoted cell proliferation and upregulates apoptosis by activating p53/ AMP-activated protein kinase (AMPK )/ Tuberous Sclerosis Complex (TSC) and there by suppressing IGF-1R/Akt/ mTOR signaling pathways. The hypothesis was tested using HT-29 and SW-480 (IGF-1R constitutively expressed) human colon cancer cell lines. IGF-1 (10 nM) treatment increased (p < 0.05) cancer cell proliferation compared to the control. Resveratrol (50-150 µM) exhibited anti-proliferative properties in the presence of IGF-1 by arresting G1-S phase cell cycle progression via up-regulation of p27 and down regulation of cyclin D1 levels. Resveratrol also decreased IGF-1R levels and concurrently suppressed activation of Akt. Targeted inhibition of IGF-1R using IGF-1R siRNA also affected the proliferation pathways in a similar fashion. Resveratrol treatment induced apoptosis by elevating cleaved PARP and tumor suppressor p53 protein levels, where as IGF-1R siRNA treatment did not have any effect on apoptosis. Resveratrol activation of p53 upregulated phosphorylation of AMPK (AMP-activated protein kinase), which in turn phosphorylated TSC2, an mTOR inhibitor. Also, resveratrol suppressed two best characterized down stream targets of mTORC1 (mammalian target of rapamycin complex 1), p70S6 Kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), even in the presence of IGF-1. Our data suggests that resveratrol exerts its anti-proliferative and pro-apoptotic properties through activation of p53, which in turn suppresses IGF-1R/Akt. For the first time we show that activation of p53 also activates AMPK and uses it to phosphorylate TSC2 and thereby inhibiting mTOR signalling in vitro. We are currently investigating the chemoprotective properties of resveratrol against obesity-promoted colon carcinogenesis using in vivo models.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3900.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009