PMPMEase inhibitors as potential therapies for castration‐resistant prostate cancer (585.7)

Abstract

Castration resistance continues to pose major challenges in the management and treatment of prostate cancer. Monomeric G‐protein signaling is critical in prostate carcinogenesis. These proteins are polyisoprenylated and regulated by polyisoprenylated methylated protein methyl esterase (PMPMEase).It was hypothesized that PMPMEase regulates cell viability and migration. The purpose was to determine the effect of PMPMEase inhibition on the malignant characteristics of prostate cancer cells.The effects of PMPMEase inhibition on cell viability, proliferation, migration and gene profiling were determined with the specific PMPMEase inhibitors, L‐28 and NSL‐RD‐036.PMPMEase specific activities were 1.5 and 4.5‐fold higher in androgen‐dependent 22Rv1 and LNCaP cells and 1.5‐ and 9.8‐fold higher in androgen‐independent DU 145 and PC‐3 prostate cancer cells compared to normal WPE1‐NA22 prostate cells. Treatment of the cells for 48 h with L‐28 induced apoptosis with EC50 values ranging from 1.8 to 4.6 µM. The PMPMEase activity in the treated cells followed a similar profile with EC50 values from 2.3 to 130 µM. L‐28 treatment significantly disrupted F‐actin cytoskeleton in PC‐3 cells and inhibited cell migration. NSL‐RD‐036 inhibited PC‐3 proliferation with an EC50 of 2 μM. The expression of cell proliferation, metastasis, apoptosis and DNA synthesis and repair genes were significantly altered by specific PMPMEase inhibition.PMPMEase inhibition induces apoptosis, disrupts F‐actin and suppresses the migration of androgen‐independent prostate cancer cells. Inhibition and measurement of PMPMEase has the potential to serve in the effective management of aggressive prostate cancer.Grant Funding Source: Supported by National Center for Research Resources and the National Institute of Minority Health an