Omega-3 Fatty Acid Inhibition of Prostate Cancer Progression to Hormone Independence Is Associated With Suppression of mTOR Signaling and Androgen Receptor Expression

Abstract

Currently, progression of prostate cancer to androgen independence remains the primary obstacle to improved survival. In order to improve overall survival, novel treatment strategies that are based upon specific molecular mechanisms that prolong the androgen-dependent state and that are useful for androgen-independent disease need to be identified. Both epidemiological as well as preclinical data suggest that omega-3 fatty acids are effective primary tumor prevention agents; however, their efficacy at preventing and treating refractory prostate cancer has not been as thoroughly investigated. We used an in vitro model of androgen ablation to determine the effect of treatment with omega-3 fatty acids on the progression to an androgen-independent state. The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were able to prevent progression of LNCaP cells while the omega-6 fatty acid arachidonic acid (AA) actually promoted cell growth under conditions of hormone depletion. These results correlated with a decrease in the expression of the androgen receptor as well as suppression of the Akt/mTOR signaling pathway. Connecting the mechanisms by which omega-3 fatty acids affect phenotypic outcome is important for effective exploitation of these nutrient agents as a therapeutic approach. Understanding these processes is critical for the development of effective dietary intervention strategies that improve overall survival.

Marine- and plant-derived ω-3 fatty acids differentially regulate prostate cancer cell proliferation

“…An increase in dietary ω-3 fatty acids has been linked to good prostate health (3,32) and prevention of prostate cancer progression to androgen independence (33). In general, there is good concurrence that fish oil is beneficial in reducing the risk of prostate cancer.…”

Omega-3 polyunsaturated fatty acid promotes the inhibition of glycolytic enzymes and mTOR signaling by regulating the tumor suppressor LKB1

“…Among the various dietary products that have been implicated in promoting health are the dietary omega-3 and omega-6 polyunsaturated fatty acids (ω3PUFAs/ω6PUFAs). ω3PUFAs have been shown to contribute to the prevention of many cancers, including breast, prostate, and colon cancers; 9,10 however, the anti-tumorigenic activity of ω3PUFAs is not fully understood.…”

Effects of arsenite on macropinocytotic and autophagic activities in CHO-K1 cells

“…A combination of indol-3-carbinol and genistein synergistically induces apoptosis and autophagy in human colon cancer HT-29 cells by inhibiting Akt phosphorylation [37]. Friedrichs et al indicated that polyunsaturated fatty acids can prevent the progression of prostate cancer cells to hormone independence by modifying signal transduction pathways such as the Akt/mTOR pathway [28]. An intact PI3K/Akt pathway is required for LNCaP cells to progress to hormonerefractory state, and Akt activity increases as the cells transform from hormone-dependent to hormone-independent [6].…”