Abstract 59: Impact of omega-3 fatty acids on obesity-induced DNA oxidation and prostate cancer progression

Abstract

Abstract Obesity is associated with poor prognosis and contributes significantly to prostate cancer-related mortality. As the prevalence of obesity increases among young adult males, the contribution to prostate cancer progression and mortality are expected to rise dramatically. One potential mechanism by which obesity may promote worse outcome is through the induction of functional metabolic abnormalities known to promote inflammation and oxidative stress. Pre-clinical and clinical observations indicate that a BMI >30 promotes oxidative DNA damage and is associated with shorter time to PSA failure and prostate cancer mortality. Growing evidence supports a beneficial role of omega-3 (ω-3) fatty acids in delaying time to PSA failure and reducing the aggressiveness of advanced prostate cancer, however, the mechanisms are multivariate and relatively unresolved. As oxidative burden is strongly implicated in the pathogenesis of age-related diseases, including prostate cancer tumor formation, and as omega-3 fatty acids possess known antioxidant and anti-inflammatory properties, we investigated the effects of docosahexaenoic acid (DHA-22:6n-3), one component of fish oil, in reducing the effects of obesity-induced oxidative DNA damage. Preliminary data demonstrates that prostate cancer cells (LNCaP) pretreated with ω-3 fatty acids and pulsed with physiologic levels of H2O2 were preferentially sensitive to induction of growth arrest compared to normal prostate epithelial cells (PrEC). LNCaP cells pulsed with 32 uM H2O2 exhibit DNA breaks associated with translocation of NF-κB into the nucleus, whereas pretreatment with DHA prior to H2O2 treatment prevented NF-κB translocation, selectively sensitizing LNCaP cells, but not PrEC, to cell death. Further, DHA attenuated H2O2-induced NF-κB transcriptional activity and diminished expression of the downstream target, survivin. NF-κB is heavily implicated in promoting prosurvival signaling and may be critical for resistance to the chronic oxidative stress and inflammation observed in the pathogenesis of prostate cancer. Here we describe one potential mechanism by which obesity may contribute to prostate cancer and the role of ω-3 fatty acids in mitigating these affects, ultimately setting the stage for Phase III clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 59.