G-protein coupled receptor-30(GPR30):a putative new therapeutic target for PCa

G蛋白偶联受体30（GPR30）：前列腺癌的假定新治疗靶点

• 批准号: 8253504
• 负责人: Shuk-Mei Ho
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253504
• 关键词: 5' Flanking Region; Ablation; Advanced Malignant Neoplasm; Affect; Affinity; Aftercare; Age; Agonist; Anchorage-Independent Growth; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Apoptosis; Binding; Biological; Brachytherapy; Breast; Cancer Patient; Cardiovascular system; Caring; Castration; Cell Proliferation; Cell membrane; Cells; Chin; Clinic; Clinical; Collaborations; Colon; Combination Drug Therapy; Country; Cox Proportional Hazards Models; DNA; DNA Methylation; DU145; Data; Databases; Deacetylase; Deoxycytidine; Development; Diagnosis; Disease Resistance; Early treatment; Endoplasmic Reticulum; Environment; Estrogens; Failure; Family; Foundations; Future; G-Protein-Coupled Receptors; Gene Expression; General Hospitals; Gleason Grade for Prostate Cancer; Growth; Health; Health system; Healthcare; Healthcare Systems; Histone Acetylation; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Immune Sera; In Vitro; Incidence; LNCaP; Letters; Life; Ligands; Logistic Regressions; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Massachusetts; Mediator of activation protein; Medical; Medical center; Military Personnel; Mission; Modeling; Mus; Mutate; Neoplasm Metastasis; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Organ; Paper; Pathology; Patient Care; Patients; Population; Postoperative Period; Prevalence; Prognostic Marker; Prostate; Prostate Cancer therapy; Prostate-Specific Antigen; Publishing; Quality of life; Recurrent tumor; Regimen; Regulation; Regulator Genes; Repression; Research; Research Personnel; Role; Services; Signal Transduction; Skin Carcinoma; Small Interfering RNA; Specimen; Staging; Study models; System; Testing; Therapeutic Intervention; Time; Tissue Microarray; Toxic effect; Translations; Treatment Protocols; Trichostatin A; Validation; Variant; Veterans; Xenograft Model; Xenograft procedure; base; beneficiary; cancer cell; cancer therapy; cell growth; cell growth regulation; cell killing; cell type; chemotherapy; cohort; comparative efficacy; cost; deprivation; design; effective therapy; estrogenic activity; follow-up; human GPRC5C protein; improved; in vitro Assay; in vivo; inhibitor/antagonist; mRNA Expression; male; medical schools; men; migration; new therapeutic target; non-genomic; novel; prognostic; quinoline; receptor; research study; response; small hairpin RNA; therapeutic target; therapy resistant; trend; tumor growth; urologic

DESCRIPTION (provided by applicant): Prostate cancer (PCa) has major impacts on veterans' health care and its incidence will continue to grow as the population ages. Despite continual progress in the development of PCa therapies, patients with androgen-deprivation-therapy (ADT)-resistant disease have limited options. Perenteral estrogens with reduced cardiovascular toxicities have shown promise in PCa treatment in recent years. An orphan G protein-coupled receptor (GPR30) with high-affinity and low-capacity binding to estrogens was identified at both the plasma membrane and the endoplasmic reticulum. This receptor is believed to be the key mediator of the non-genomic action of estrogens. Upon its binding to ligand, GPR30 either stimulates or inhibits cell proliferation in an ER- independent, cell type-specific manner. The identificaion of G-1 (1-[4-(6-bromobenzo[1,3]dioxol-5yl)-3a,4,5,9b- tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone) as a GPR30-selective agonist with no estrogenic activity provides a unique opportunity to elucidate the biological significance of GPR30 in cell growth regulation, especially in cells that express ER1 and/or ER2. Using G-1, and confirmed by siRNA knockdown experiments, we recently demonstrated strong inhibitory effects of G-1 on the growth of AD and ADT-resistant PCa cells in culture. It also inhibited PC-3 xenograft growth in nude mice. A trend of reduction of GPR30 mRNA expression was observed in PCa clinical specimens when compared to their adjacent normal tissues although the degree of expression varies a great deal among PCa specimens. Treatment of PCa cells with 5-aza-2'-deoxycytidine, a demethylating agent, tricostatinA, a HDACi, or an ADT increased GPR30 expression. Based on these novel findings, we here hypothesize that activation of GPR30 signaling via its specific ligand G-1, either alone or in combination with a demethylating agent, a histone deacetylase inhibitor (HDACi), or androgen ablation, is an effective anti-PCa therapy, and that GPR30 has prognostic value in PCa. Three aims are proposed to test this hypothesis. Objective 1: Establish the role of GPR30 in G-1-induced growth inhibition/cell kill in AD and ADT- resistant PCa cells under in vitro and in vivo settings. Objective 2: Determine whether DNA methylation, histone deacetylation, or androgen repression are involved in the regulation of GPR30 expression and compare the efficacies of G-1, alone or in combination with one of these agents in curbing PCa growth. Objective 3: Evaluate the prognostic value of GPR30 expression in PCa. This project will provide the first evidence in support of GPR-30 as a novel PCa therapeutic target and lay down a foundation for future development of GPR30-based therapies for PCa. PUBLIC HEALTH RELEVANCE: Prostate cancer affects one out of six men in their life time and has significant impacts on veterans' health care. The main thrust of this research is to design a new class of prostate cancer therapies based on our understanding of a G-coupled protein receptor known as GPR30. The research is relevant to the treatment of early stage and advanced stage prostate cancer and may establish GPR30 as a prognostic marker for prostate cancer.

描述（由申请人提供）： 前列腺癌（PCa）对退伍军人的医疗保健有重大影响，随着人口老龄化，其发病率将继续增长。尽管PCa疗法的开发不断取得进展，但雄激素剥夺疗法（ADT）耐药疾病患者的选择有限。近年来，具有降低心血管毒性的经肠给药雌激素在PCa治疗中显示出前景。一个孤儿G蛋白偶联受体（GPR 30）与雌激素的高亲和力和低容量的结合被确定在质膜和内质网。这种受体被认为是雌激素非基因组作用的关键介质。在其与配体结合后，GPR 30以ER非依赖性、细胞类型特异性的方式刺激或抑制细胞增殖。G-1（1-[4-（6-溴苯并[1，3]间二氧杂环戊烯-5基）-3a，4，5，9 b-四氢-3H-环戊二烯并[c]喹啉-8-基]-乙酮）作为GPR 30选择性激动剂的鉴定不具有雌激素活性，这为阐明GPR 30在细胞生长调节中的生物学意义提供了独特的机会，特别是在表达ER 1和/或ER 2的细胞中。使用G-1，并通过siRNA敲除实验证实，我们最近证明了G-1对培养的AD和ADT抗性PCa细胞生长的强烈抑制作用。它还抑制PC-3异种移植物在裸鼠中的生长。GPR 30 mRNA在PCa临床标本中的表达与癌旁正常组织相比呈下降趋势，但不同PCa标本中GPR 30 mRNA的表达水平差异很大。用5-氮杂-2 '-脱氧胞苷、去甲基化剂、曲可他汀A、HDACi或ADT处理PCa细胞增加GPR 30表达。基于这些新的发现，我们在此假设，通过其特异性配体G-1激活GPR 30信号传导，单独或与去甲基化剂、组蛋白去乙酰化酶抑制剂（HDACi）或雄激素消融联合使用，是一种有效的抗PCa治疗，并且GPR 30在PCa中具有预后价值。提出了三个目标来检验这一假设。 目标一：在体外和体内环境下，确定GPR 30在AD和ADT抗性PCa细胞中G-1诱导的生长抑制/细胞杀伤中的作用。 目标二：确定是否DNA甲基化，组蛋白去乙酰化，或雄激素抑制参与GPR 30表达的调节，并比较G-1，单独或与这些药物之一在抑制PCa生长的疗效。 目的3：探讨GPR 30在前列腺癌中的表达及其预后价值。该项目将首次提供支持GPR-30作为PCa治疗新靶点的证据，并为未来开发基于GPR-30的PCa治疗方法奠定基础。 公共卫生相关性： 前列腺癌影响六分之一的男性，对退伍军人的医疗保健有重大影响。这项研究的主要目的是根据我们对G偶联蛋白受体GPR 30的理解，设计一类新的前列腺癌治疗方法。该研究与早期和晚期前列腺癌的治疗相关，并可能将GPR 30作为前列腺癌的预后标志物。