Regulation of prostate cancer cell survival by 5-lipoxygenase:Role of PKC-epsilon

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DESCRIPTION (provided by applicant): Regulation of prostate cancer cell survival by 5-lipoxygenase: Role of PKC-epsilon Fresh experimental data suggest that induction of apoptosis in prostate cancer (PCa) cells by blocking critical survival mechanism(s) can be an attractive approach to prevent and treat PCa because clinically PCa is often characterized as slow growing where anti-mitogenic therapies are not much effective. However, the repertoire of survival mechanisms in PCa cells is not completely understood which largely contributes to the loss of battle against this disease. Emerging evidence from various studies has shown that PCa cells constitutively generate metabolites of 5-lipoxygenase (5-Lox) from arachidonic acid (an omega-6 fatty acid plentiful in Western diets), and inhibition of 5-Lox by specific inhibitors blocks production of 5-Lox metabolites and induces rapid apoptosis both in androgen-sensitive as well as androgen-independent PCa cells sparing non-cancer cells. Apoptosis is effectively prevented by the 5-Lox metabolites, 5(S)-HETE and 5-oxoETE, suggesting that these metabolites play an essential role in the survival of PCa cells. A critical role of 5-Lox in the survival of PCa cells has also been documented using siRNAs against 5-Lox. However, signaling mechanism(s) through which 5-Lox metabolites regulate PCa cell survival are not yet understood. Interestingly, 5-Lox is not expressed in normal prostate glands but is highly expressed in prostate tumors and in PCa cells, which together with a critical role of 5-Lox in the survival of PCa cells, suggests that 5-Lox may play an important role in the development of PCa. A recent pilot experiment showed that MK591, a specific inhibitor of 5-Lox activity, remarkably blocks prostate tumor growth in nude mice xenografts without any toxicity to animal health, suggesting that inhibition of 5-Lox could be an attractive approach for mounting specific attack on PCa cells without general toxicity. Thus, in vivo targeting of 5-Lox should be extensively carried out for a rapid translational development against PCa. The goals of this research project are to delineate the signaling mechanisms underlying regulation of PCa cell survival by 5-Lox, and to test the in vivo effects of targeting 5-Lox focusing on both the preventive and therapeutic aspects of PCa. These goals will be achieved by accomplishing the objectives of three specific aims. Specific Aim 1 will determine how 5-Lox activity regulates PCa cell survival involving PKC-epsilon (PKC5)-mediated signaling, because inhibition of 5-Lox inhibits PKC5 which is prevented by 5-Lox metabolites, and 5-Lox inhibition-induced apoptosis is prevented by activators of PKC5. Specific Aim 2 will determine whether inhibition of 5-Lox inhibits growth of prostate tumors in nude mice xenografts via induction of apoptosis in PCa cells. Specific Aim 3 will determine the role of 5-Lox in the development and progression of PCa by generating 5-Lox knockout transgenic (TRAMP) mice. Accomplishing the goals in this research project will help us to understand a novel mechanism of PCa cell survival, to determine whether 5-Lox plays a role in the development and progression of PCa, and to test whether targeting 5-Lox could be a novel mechanism-based strategy for prevention as well as treatment of PCa.