Regulator of G-protein Signaling (RGS) Proteins in Prostate Cancer

描述（由申请人提供）：异常的G蛋白偶联受体（GPCR）信号导致包括癌症在内的许多人类疾病。g蛋白信号（RGS）蛋白调控因子抑制GPCR信号。这项应用的长期目标是阐明RGS蛋白在肿瘤发生中的作用。前列腺癌是男性最常见的癌症，获得雄激素独立性是前列腺癌进展的关键问题。一些证据表明雄激素受体（AR）的雄激素非依赖性激活是潜在的机制之一。最近的研究表明，激素通过G蛋白偶联受体（gpcr）引起雄激素非依赖性AR激活。我们最近报道了RGS超家族成员RGS2通过GPCR信号选择性抑制前列腺癌细胞中雄激素非依赖性AR激活。有趣的是，在已建立的前列腺癌细胞系中，RGS2蛋白表达与雄激素非依赖性细胞增殖呈负相关。此外，与正常前列腺组织相比，人类前列腺癌标本的RGS2水平显著降低。因此，我们假设RGS2作为一种新的AR信号调节因子，其抑制是前列腺肿瘤发生和发展的重要步骤。

DESCRIPTION (provided by applicant): Aberrant G protein-coupled receptor (GPCR) signaling causes many human diseases including cancer. Regulator of G-protein signaling (RGS) proteins inhibit GPCR signaling. The long-term goal of this application is to elucidate the roles of RGS proteins in tumorigenesis. Prostate cancer is the most common cancer in men and acquisition of androgen independence by prostate cancer is the key problem of prostate cancer progression. Several lines of evidence suggest that androgen-independent activation of androgen receptor (AR) is one of underlying mechanisms. Recent studies demonstrate that hormones acting through G protein-coupled receptors (GPCRs) cause androgen-independent AR activation. We recently reported that RGS2, a member of RGS superfamily, selectively inhibits androgen-independent AR activation by GPCR signaling in prostate cancer cells. Interestingly, RGS2 protein expression was inversely correlated with the androgen-independent cell proliferation in established prostate cancer cell lines. In addition, human prostate cancer specimens had significantly lower levels of RGS2 compared to normal prostate tissues. Thus, we hypothesize that RGS2 functions as a novel regulator of AR signaling and its repression is an important step in prostate tumorigenesis and progression. Specific Aims: 1. To assess the biological importance of RGS2 repression in prostate cancer cells. 2. To determine the molecular mechanism underlying RGS2-mediated inhibition of androgen-independent prostate cancer growth. 3. To elucidate the mechanism underlying RGS2 repression in prostate cancer. Research Design and Methods: We will first examine the effects of altering RGS2 expression on the androgen-independent growth of prostate cancer cells in culture and in castrated athymic nude mice. We will then pinpoint the amino acids of RGS2 critical for its selective inhibition of androgen-independent AR activation and cell growth in prostate cancer cells and identify the AR domains responsible for its regulation by RGS2. Finally, we will combine methylation-specific PCR and immunohistochemistry analysis to investigate whether methylation of the RGS2 gene is responsible for RGS2 repression in prostate cancer. The feasibility of using RGS2 expression and/or RGS2 methylation status as a novel marker for diagnosis and prognosis of prostate cancer will then be evaluated. In addition to methylation, we will also explore whether genetic alterations or histone modifications contribute to RGS2 repression in prostate cancer. Information on the biological importance of RGS2 in the regulation of prostate cancer progression is directly relevant to understanding the biology of prostate cancer. Completion of the proposed studies will not only provide a potential diagnostic and prognosis marker for prostate cancer progression but will also allow the development of novel drugs for the treatment of prostate cancers.