Prostate cancer is the second leading cause of cancer related deaths in men. The primary obstacle in effective treatment of prostate cancer is the progression of the disease from a hormone-dependent to a hormone-independent state. Previous studies indicate that activation of the mammalian Target of Rapamycin (mTOR) signaling pathway may be involved in progression of prostate cancer to androgen independence. Recent data indicate that the combination of androgen deprivation with mTOR inhibition provides an additive anti-tumor effect in vivo. mTOR activity is regulated by both growth factors and nutrients, suggesting that certain dietary interventions may have anti-cancer effects through regulation of mTOR. Epidemiological studies indicate an inverse relation between dietary intake of omega-3 fatty acids and prostate cancer risk. Omega-3 fatty acids have been shown to inhibit prostate cell growth both in vitro and in vivo. Preliminary data from our laboratory demonstrated that treatment of LNCaP prostate cancer cells with omega-3 fatty acids, specifically docosahexaonoic acid (DHA), delayed development of androgen independence in vitro. This delay correlated with a decrease in protein expression of downstream targets of mTOR regulation, including phosphorylated S6, Bcl-2, and cyclin D. We hypothesize that omega-3 fatty acids may prevent prostate cancer progression to a hormone independent phenotype in part through modulation of mTOR. To test this hypothesis, we established stable transfectant LNCaP cell lines that express a constitutively active mTOR. These clones displayed less sensitivity to hormone deprivation, resembling the response observed in our previously generated hormone refractory LNCaP cell line. Importantly, these clones with constitutively active mTOR also showed resistance to the inhibitory effects of DHA. Ongoing studies are using these clones to determine if omega-3 fatty acids mediate their effect on mTOR in an Akt-independent manner to delay progression of prostate cancer to a hormone refractory phenotype. We will investigate alternative pathways through which mTOR activity is modulated in prostate cancer signaling, These studies indicate that mTOR is critical for cellular response to hormone ablation, and that mTOR may be a viable target for delaying progression to a hormone refractory disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5574. doi:10.1158/1538-7445.AM2011-5574