Docosahexaenoic Acid Selectively Induces Human Prostate Cancer Cell Sensitivity to Oxidative Stress Through Modulation of NF-κB

BACKGROUND. Oxidative burden is strongly implicated in the pathogenesis of age-related diseases, including prostate cancer tumor formation. As omega-3 fatty acids possess known antioxidant properties, we investigated the effects of docosahexaenoic acid (DHA-22:6n-3), one component of fish oil, in modulating the effects of oxidative DNA damage in LNCaP and PacMetUT1 human prostate adenocarcinoma cells and in a normal human prostate cell line, PrEC. METHODS. Cell survival was determined by an inhibition of colony formation assay. DNA double-strand breaks, NF-kappa B subcellular localization and relative survivin expression levels were determined by immunofluorescence and survivin expression levels confirmed by immunoblot assay. Measurement of NF-kappa B transcriptional activity was investigated by dual luciferase assay. RESULTS. LNCaP and PacMetUT1 cells pretreated with DHA and pulsed with 32 mu M H2O2 exhibit decreased survival compared to PrEC. gamma-H2AX foci, indicating DNA double-strand breaks, were associated with translocation of NF-kappa B into the nucleus, whereas exposure to DHA prior to H2O2 treatment prevented NF-kappa B translocation. Further, DHA attenuated H2O2-induced NF-kappa B transcriptional activity and diminished expression of the downstream target, survivin. CONCLUSIONS. NF-kappa B is heavily implicated in promoting prosurvival signaling and may be critical for resistance to the chronic oxidative stress observed in the pathogenesis of prostate cancer. Our studies indicate that exposure of cells to physiologically achievable levels of DHA prior to treatment with H2O2 results in decreased cancer cell survival which is associated with nuclear exclusion of NF-kappa B. We therefore propose that DHA selectively sensitizes prostate cancer cells to growth arrest through attenuation of the NF-kappa B survival pathway. Prostate 71: 1420-1428, 2011. (C) 2011 Wiley-Liss, Inc.