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.
Regulation of prostate cancer cell survival by 5-lipoxygenase: Role of PKC-epsilon Emerging evidence from our own studies and others has shown that prostate cancer cells constitutively generate metabolites of 5-lipoxygenase (5-Lox) and inhibition of 5-Lox blocks the production of 5-Lox metabolites and induces rapid apoptosis both in androgen-sensitive as well as in androgen-independent prostate cancer cells sparing normal, non-cancer cells. Interestingly, it was observed that 5-Lox is not expressed in normal, non-cancer prostate glands, but is highly expressed in prostate tumor tissues and in cultured prostate cancer cells, suggesting that 5-Lox may play an important role in prostate cancer development. Thus, 5-Lox has emerged as an attractive, novel target for prostate cancer control. However, signaling mechanism(s) through which 5-Lox metabolites regulate prostate cancer cell survival are yet to be understood, and extensive in vivo testing of targeting 5-Lox are needed to develop novel strategies for prevention and therapy of prostate cancer. Our preliminary observations suggest that 5-Lox activity regulates protein kinase C-epsilon (PKC5) and PKC5 is a potential mediator of the survival-promoting effects of 5-Lox metabolites. Thus, this project has been designed to understand a novel mechanism of prostate cancer cell survival regulated by 5-Lox, and to test the in vivo effects of targeting 5-Lox by novel agents and strategies for prevention as well as treatment of prostate cancer.
|Sarveswaran, Sivalokanathan; Ghosh, Ritisha; Parikh, Rujul et al. (2016) Wedelolactone, an Anti-inflammatory Botanical, Interrupts c-Myc Oncogenic Signaling and Synergizes with Enzalutamide to Induce Apoptosis in Prostate Cancer Cells. Mol Cancer Ther 15:2791-2801|
|Sarveswaran, Sivalokanathan; Ghosh, Ritisha; Morisetty, Shravan et al. (2015) MK591, a second generation leukotriene biosynthesis inhibitor, prevents invasion and induces apoptosis in the bone-invading C4-2B human prostate cancer cells: implications for the treatment of castration-resistant, bone-metastatic prostate cancer. PLoS One 10:e0122805|
|Sarveswaran, Sivalokanathan; Chakraborty, Debrup; Chitale, Dhananjay et al. (2015) Inhibition of 5-lipoxygenase selectively triggers disruption of c-Myc signaling in prostate cancer cells. J Biol Chem 290:4994-5006|
|Sarveswaran, Sivalokanathan; Ghosh, Jagadananda (2013) OXER1, a G protein-coupled oxoeicosatetraenoid receptor, mediates the survival-promoting effects of arachidonate 5-lipoxygenase in prostate cancer cells. Cancer Lett 336:185-95|
|Sarveswaran, Sivalokanathan; Gautam, Subhash C; Ghosh, Jagadananda (2012) Wedelolactone, a medicinal plant-derived coumestan, induces caspase-dependent apoptosis in prostate cancer cells via downregulation of PKCÎµ without inhibiting Akt. Int J Oncol 41:2191-9|
|Sarveswaran, Sivalokanathan; Thamilselvan, Vijayalakshmi; Brodie, Chaya et al. (2011) Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon. Biochim Biophys Acta 1813:2108-17|