Abstract 418: Polyisoprenylated methylated protein methyl esterase overexpression in prostate cancer: implication in cancer metastasis.

Abstract

Abstract Objectives: Prostate cancer is the most frequently diagnosed cancer among men in the U.S, with an estimated 241,740 new cases and 28,170 deaths for 2012. The need to identify biomarkers/therapeutic targets for the early/companion diagnosis and development of novel therapies against the recalcitrant form of prostate cancer is imperative. Mutation and overexpression-induced abnormal activities of polyisoprenylated proteins such as of the Ras and Rho families of monomeric G proteins have been implicated in prostate cancer. Also, signaling mediated by polyisoprenylated Rho family of GTPases through the actin cytoskeleton in migratory responses is necessary for cancer cell metastasis. Polyisoprenylated methylated protein methyl esterase (PMPMEase) catalyzes the only reversible and terminal reaction of the polyisoprenylation pathway. We hypothesized that PMPMEase activity may influence the effects of these G proteins on cell viability, metastasis and aggressiveness and thus may be of importance in the detection and treatment of prostate cancer. Method: Prostate cancer tissue microarray was probed for relative PMPMEase expression by immunohistochemistry. Specific activities of PMPMEase and the effect of its inhibition on viability of various prostate cancer cells were also studied. Effect of specific PMPMEase inhibitor L-28 on actin cytoskeleton organization was also determined by phalliodine staining of treated PC-3 cells. Results: PMPMEase specific activities were 4 and 6-fold higher in androgen-dependent 22Rv1 and LNCaP cells and 2- and 17-fold higher in androgen-independent PC-3 and DU 145 prostate cancer cells respectively compared to normal WPE1-NA22 prostate cells. Treatment of the cells for 72 h with L-28, a specific polyisoprenylated PMPMEase inhibitor induced apoptosis with EC50 values ranging from 1.8 to 4.6 μM. The PMPMEase activity of the different cell lines followed a similar profile with IC50 values ranging from 2.3 to 130 μM. L-28 also significantly disrupted the actin filament arrangement. Immunohistochemical analysis of PMPMEase expression revealed intermediate, strong and very strong staining in 94.5% of the 92 adenocarcinoma cases compared to only trace and weak staining in the normal and normal adjacent tissue controls. Conclusion: These results indicate that PMPMEase activity, immunoreactivity and inhibition could serve in the diagnosis and targeted therapeutic management of prostate cancer. Also inhibition of PMPMEase disturbs actin filament organization in cytoskeleton. Citation Format: Rosemary A. Poku, Felix Amissah, Randolph Duverna, Byron J. Aguilar, Nazarius S. Lamango. Polyisoprenylated methylated protein methyl esterase overexpression in prostate cancer: implication in cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 418. doi:10.1158/1538-7445.AM2013-418