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Polyisoprenylated Methylated Protein Methyl Esterase as a Putative Biomarker and Drug Target for Prostate Cancer
Başlık:
Polyisoprenylated Methylated Protein Methyl Esterase as a Putative Biomarker and Drug Target for Prostate Cancer
Yazar:
Poku, Rosemary A., author.
ISBN:
9780438009134
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (136 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Nazarius S. Lamango Committee members: Edward Agyare; Selina Darling-Reed; Hernan Flores-Rozas; Anthony Ndifor; Romonia R. Reams.
Özet:
Prostate cancer (PCa) is the most frequently diagnosed cancer in U.S. men, with an estimated 180,890 new cases to be diagnosed in 2016, and 26,120 men are expected to die of this malignancy. Metastatic castration-resistant prostate cancer (mCRPC) poses a major challenge to chemotherapy and it accounts for all prostate cancer-related deaths. With a constantly growing patient population with mCRPC, there is an important unmet need for novel therapies targeting molecular entities that drive mCRPC. This dissertation aims to evaluate the potential anti-mCRPC effectiveness of selected polyisoprenylated compounds.
mCRPC is characterized by the overexpression of epidermal growth factor receptors whose signals are mediated by G proteins of the Ras superfamily that require polyisoprenylation for functional activity. Mutation and overexpression-induced abnormal activities of polyisoprenylated proteins have been implicated in prostate cancer. Polyisoprenylated methylated protein methyl esterase (PMPMEase) co-catalyzes the only reversible and terminal reaction of the polyisoprenylation pathway and may regulate the effects of G proteins on cell viability, survival and metastasis. In this study, the potential role of PMPMEase as a new drug target for mCRPC was determined. Specific intracellular PMPMEase activities were found to be 1.5- and 4.5-fold higher in androgen-dependent 22Rv1 and LNCaP prostate cancer cells, respectively compared to normal WPE1-NA22 prostate cells. Relatively higher activities of 1.5- and 9.8-fold compared to normal prostate cells were observed in androgen-independent DU 145 and PC 3 prostate cancer cells. The PMPMEase inhibitor, L-28 induced apoptosis with EC 50 values ranging from 1.8 to 4.6 microM. The PMPMEase activity in the L-28-treated cells followed a similar profile, with IC50 values ranging from 2.3 to 130 microM. L-28 disrupted F-actin filament organization at 5 microM and inhibited cell migration by over 50% at 1 microM. Analysis of a prostate cancer 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 tissues. The data is an indication that effective targeting of PMPMEase through the development of more potent agents may lead to more effective management of mCRPC.
Furthermore the second generation of potential PMPMEase inhibitors, the polyisoprenylated cysteinyl amide inhibitors (PCAIs) was developed to alter polyisoprenylated protein metabolism and/or functional interactions as a means to mitigate excessive growth signaling in cancer cells. We investigated the effects of PCAIs; NSL-RD-036, NSL-BA-040, NSL-BA-055 and NSL-BA-056 on the viability of prostate cancer cell lines (PC 3, DU 145, MDA PCa 2b, LNCaP and 22Rv1). Also, the effects of PCAIs on PC 3 cell proliferation, survival and caspase 3/7 activation were determined. Metastatic PC 3 and DU 145 cell migration and invasion in the presence of NSL-RD-040 were determined using the scratch and matrigel invasion assays. We further investigated the effect of NSL-RD-040 on F-actin organization in TagRFP F-actin marker transfected metastatic PC 3 cells. The PCAIs exhibited concentration-dependent cytotoxicity in all the prostate cancer cell lines. NSL-BA-040 showed the highest activity (EC 50 1.3-4.0 microM) followed by NSL-BA-055 (EC50 1.5-4 3 microM), NSL-RD-036 (EC50 4.7- 6.3 microM) and NSL-BA-056 (EC 50 5.1-15 microM). PCAIs also inhibited metastatic PC 3 cell proliferation in a concentration-dependent manner, completely halting PC 3 cell proliferation at 2 microM. Exposure of PC 3 cells to 2-5 microM of NSL-BA-040 induced caspase 8 and 3 mediated apoptosis and disrupted F-actin cytoskeleton organization in TagRFP F-actin marker transfected metastatic PC 3 cells. NSL-RD-040 at 2.0 microM inhibited PC 3 and DU 145 cell migration (p< 0.01) and invasion (p< 0.01) through matrigel by 40% and 94%, respectively.Thus the PCAIs exhibit anti-cancer effects in mCRPC cells, at least in part through the induction of caspase-mediated apoptosis and inhibition of F-actin-mediated cell motility and invasion.
Collectively, these demonstrate that PMPMEase activity is essential for cell survival and excessive activities are likely to promote tumor growth and metastasis. These findings present PMPMEase as an attractive diagnostic biomarker and target for therapeutic drug development. Although PCAIs performed poorly against the enzyme activity, their superior effects against cell viability and proliferation suggest that they likely disrupt signaling by such polyisoprenylated monomeric G-proteins proteins as Rho, Rac and cdc42 proteins that are involved in F-actin organization and metastasis. Thus the PCAIs could be developed into therapeutic agents for effective management of mCRPC.
Notlar:
School code: 0872
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(677896.1) | 677896-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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