Abstract
Prostate cancer (CaP) is the most frequently diagnosed cancer in US men, with an estimated 236,590 new cases and 29,720 deaths in 2013. There exists the need to identify biomarkers/therapeutic targets for the early/companion diagnosis and development of novel therapies against the recalcitrant disease. Mutation and overexpression-induced abnormal activities of polyisoprenylated proteins have been implicated in CaP. Polyisoprenylated methylated protein methyl esterase (PMPMEase) catalyses the only reversible and terminal reaction of the polyisoprenylation pathway and may promote the effects of G proteins on cell viability. In this review, the potential role of PMPMEase to serve as a new drug target for androgen-insensitive CaP was determined. Specific PMPMEase activities were found to be 3.5- and 4.5-fold higher in androgen-sensitive 22Rv1 and androgen-dependent LNCaP and 1.5- and 9.8-fold higher in castration-resistant DU 145 and PC-3 CaP cells compared to normal WPE1-NA22 prostate cells. The PMPMEase inhibitor, L-28, induced apoptosis with EC50 values ranging from 1.8 to 4.6 μM. The PMPMEase activity in the cells following treatment with L-28 followed a similar profile, with IC50 ranging from 2.3 to 130 μM. L-28 disrupted F-actin filament organisation at 5 μM and inhibited cell migration 4-fold at 2 μM. Analysis of a CaP tissue microarray for PMPMEase expression revealed intermediate, strong, and very strong staining in 94.5% of the 92 adenocarcinoma cases compared to trace and weak staining in the normal and normal-adjacent tissue controls. The data are an indication that effective targeting of PMPMEase through the development of more potent agents may lead to the successful treatment of metastatic CaP.
Highlights
Castration-resistant prostate cancer (CRPC) continues to be a major challenge in the therapeutic management of prostate cancer (CaP)
PMPMEase protein and enzymatic activity levels are elevated in CaP cells Incubation of the specific PMPMEase substrate, RD-PNB, with lysates from the respective cell lines resulted in the hydrolysis of the substrate to the product as determined by HPLC analysis with UV detection (Figure 1A)
When the various CaP cell lines were lysed and aliquots containing identical amounts of protein were analysed by western blotting, PMPMEase was observed to be highly expressed in the castration resistant DU 145 and PC-3 cells compared to the normal prostate, androgen-dependent LNCaP and androgen-sensitive 22Rv1 cells (Figure 1C)
Summary
Castration-resistant prostate cancer (CRPC) continues to be a major challenge in the therapeutic management of prostate cancer (CaP). Androgen deprivation has been the first-line therapy for metastatic CaP for many years [2]. This is accomplished by surgical or chemical castration [3]. A 2–3-year remission period is usually achieved, after which virtually all patients’ disease progress to an androgen-independent state that results in death within 16–18 months [2]. This CRPC is marked by rising serum prostate-specific antigen (PSA), increasing the tumour size and new metastatic capability [3]. The need for novel targets for the development of effective therapies is imperative
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