Abstract
Abstract Background: Metastatic castration-resistant prostate cancer (mCRPC) poses a major clinical management challenge due to lack of effective therapies. Monomeric G- proteins of the Ras superfamily such as Rho, Rac and Cdc42 are critical mediators in prostate cancer progression and metastasis, due to their effect on F-actin organization in cell migration. These proteins are polyisoprenylated and subject to regulation by polyisoprenylated methylated protein methyl esterase (PMPMEase). We hypothesized that metabolism of monomeric G-proteins by PMPMEase regulates growth, survival and differentiation as well as cell migration and invasion through its effects on F-actin assembly. Methods: The effects of polyisoprenylated cysteinyl amides (PCAIs), NSL-RD-036, NSL-BA-040, NSL-BA-055 and NSL-BA-056 on the viability and proliferation of prostate cancer cell lines were investigated using the MTS assay. Docetaxel and paclitaxel were used as positive controls. Metastatic PC -3 cell migration and invasion in the presence of NSL-RD-036 were determined using the scratch and matrigel invasion assays. The effect of NSL-RD-040 on F-actin organization in TagRFP F-actin marker-transfected PC 3 cells was also investigated. Results: The PCAIs were cytotoxic to all prostate cancer cell lines (PC-3, DU 145, LNCaP and 22Rv1). In all the cell lines, NSL-BA-040 showed the highest activity (EC50 4.3 - 5.0 μM) followed by NSL-RD-036 (EC50 2.0 - 9.2 μM), NSL-BA-056 (EC50 4.8 - 7.5 μM) and NSL-BA-055 (EC50 2.9 - 11.2 μM) while docetaxel and paclitaxel were not as effective (EC50 >100 μM). Metastatic PC-3 cell proliferation was inhibited in a concentration-dependent manner by NSL-RD-036 and at 2 μM PC-3 cell proliferation was halted. Exposure of PC-3 cells to NSL-BA-040 induced apoptosis and disrupted F-actin cytoskeleton organization in TagRFP F-actin marker transfected metastatic PC-3 cells. NSL-RD-036 also significantly inhibited PC-3 cell migration and invasion through matrigel. Conclusions: Polyisoprenylated small molecules suppress migration and invasion as well as disrupt F-actin organization of metastatic PC-3 cells. Polyisoprenylated small molecules could serve as a new class of therapeutic agents in metastatic castration resistant prostate cancer. Citation Format: Rosemary Aniwaa Poku, Augustine Nkembo, Olufisayo Salako, Felix Amissah, Hernan Flores-Rozas, Tryphon Mazu, Nazarius S. Lamango. Targeting metastatic prostate cancer with polyisoprenylated cysteinyl amides. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5090. doi:10.1158/1538-7445.AM2015-5090
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