Cancers originating from androgen-target tissues, such as prostate, are dependent on androgens for growth. Androgens manifest their effects by binding to and activating the androgen receptor (AR). Anti-androgen treatment inhibits the growth of prostate cancer cells. However, most prostate cancers eventually develop an androgen-independent phenotype and become resistant to anti-hormone therapy. The Akt kinase phosphorylates the AR in vitro and permits activation of the AR in the absence of androgen. It has also been observed that Akt hyperactivity is sufficient to convert AR-positive prostate cancer cells from the hormonesensitive to the resistant phenotype. Omega-3 fatty acids have long been known as potent anti-tumor agents in animal models, but the mechanisms by which they manifest these effects remain unclear. In a breast cancer model, we have demonstrated that omega-3 fatty acids inhibit Akt activity, suggesting that one mechanism by which these dietary components affect tumor growth is by blocking mitogenic signaling through the Akt pathway. From these results we hypothesize that: 1) omega-3 fatty acids are able to inhibit mitogenstimulated activation of Akt in AR-positive prostate cancer cells. 2) inhibition of Akt by omega-3 fatty acids abrogates the Akt-dependent progression from a hormone-responsive to hormone-refractory phenotype. We will address these hypotheses by first investigating the response of Akt and its downstream targets to treatment with omega-3 fatty acids in the AR-positive, androgen-dependent LnCaP prostate cancer cell line. We will assess kinase activity, and evaluate alterations in expression levels and phosphorylation statuses of both Akt and the AR as well as their respective downstream targets. We will then use an in vitro model of androgen ablation to determine whether inhibition of Akt activity by treatment with omega-3 fatty acids prevents the progression to the androgen-independent state. The results from this research application will lay the foundation for further studies investigating the use of dietary intervention to target specific molecular targets for the prevention of phenotype-specific cancers.
| Friedrichs, William; Ruparel, Shivani B; Marciniak, Robert A et al. (2011) Omega-3 fatty acid inhibition of prostate cancer progression to hormone independence is associated with suppression of mTOR signaling and androgen receptor expression. Nutr Cancer 63:771-7 |
