Introduction: Prostate cancer is the most commonly diagnosed cancer in the United States. The etiology of prostate cancer development and progression is not very clear. Accumulating evidence suggests that an elevated level of insulin-like growth factor-1 (IGF-1) is positively associated with the growth of prostate cancer. IGF-1 exerts its mitogenic effect by binding to its receptor, IGF-1R, whose expression is also increased during tumor growth. Resveratrol, a phytoalexin, has been shown to possess anti-cancer action against various cancers through unknown mechanism/s. In this study, we examined whether resveratrol mediates its anti-tumor effects by inhibiting the trophic actions of IGF-1/IGF-1R on prostate cancer.
Methods: In vitro studies were performed on highly aggressive androgen receptor negative human prostate cancer cells, PC-3M-MM2. Cell viability was assessed by MTS assays, while apoptosis was determined by Annexin-FITC and PI staining. Additionally, ELISA and western blotting techniques were performed to examine the levels of IGF-1 and protein involved in IGF-axis, respectively. In vivo efficacy of resveratrol was tested in a xenograft model of prostate cancer in severe combined immunodeficient (SCID) mice. PC-3M-MM2 cells were subcutaneously injected in these mice and resveratrol was administered by oral gavage for the assessment of tumor growth. Primary tumors were then excised and immunohistochemistry was performed on the tumor sections. Results: Resveratrol significantly inhibited the release of IGF-1 from PC-3M-MM2 cells and reduced the activation of IGF-1R. Inhibition of IGF-1R by resveratrol suppressed the activation of Akt (pAkt) and increased the expression of programmed cell death 4 (PDCD4), a pro-apoptotic protein and a target of Akt. These effects of resveratrol were associated with reduced cell viability and induction of apoptosis in PC-3M-MM2 cells. Treatment of cells with short interfering (si) RNA against IGF-1R or PI3 kinase inhibitor (LY294002) mimicked the response of resveratrol on cell viability, apoptosis and the expression of pAkt and PDCD4. Furthermore, oral administration of resveratrol in SCID mice that were subcutaneously injected with PC-3M-MM2 cells suppressed subsequent tumor growth. Resveratrol also reduced serum and tumor levels of IGF-1 and inhibited the activation of IGF-1R in these tumors. This modulation of IGF-1/IGF-1R coincided with the inhibition of pAkt and increase in PDCD4 in the tumor tissue.
Conclusion: Our results indicate that resveratrol effectively suppressed prostate cancer growth in vitro as well as in vivo by attenuating IGF-1/IGF-1R signaling pathway. These data demonstrate that the IGF/IGF-1R represent a relevant target of resveratrol for mediating its anti-tumor actions against prostate cancer.
Citation Format: Sandeep Sheth, Sarvesh Jajoo, Debashree Mukherjea, Kelly Sheehan, Leonard P. Rybak, Vickram Ramkumar. Resveratrol attenuates prostate cancer growth by inhibiting insulin-like growth factor-1 receptor signaling. [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 4084. doi:10.1158/1538-7445.AM2013-4084