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，随着人口年龄的增长，其发病率将继续增长。尽管PCA疗法的发展持续进展，但患有雄激素 - 剥夺 - 疗法（ADT）耐药性疾病的患者的选择有限。近年来，PCA治疗中的心血管毒性降低已显示出希望。在质膜和内质网均鉴定出具有高亲和力和低容量与雌激素的孤儿G蛋白偶联受体（GPR30）。该受体被认为是雌激素非基因组作用的关键介体。 GPR30与配体结合后，以独立的细胞类型特异性方式刺激或抑制细胞增殖。 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调节，特别是在表达ER1和/或ER2的细胞中。使用G-1，并通过siRNA敲低实验证实，我们最近证明了G-1对培养中AD和ADT耐药PCA细胞生长的强烈抑制作用。它还抑制了裸鼠的PC-3异种移植生长。与邻近的正常组织相比，在PCA临床标本中观察到了GPR30 mRNA表达的降低趋势，尽管表达程度在PCA标本中有很大变化。用5-Aza-2'-脱氧胞苷，脱甲基化剂，Tricostatina，HDACI或ADT增加GPR30表达的PCA细胞。基于这些新的发现，我们在这里假设GPR30信号通过其特定的配体G-1单独或与脱甲基化剂，组蛋白脱乙酰基酶抑制剂（HDACI）或雄激素消融的激活是有效的抗PCA疗法，是有效的抗PCA疗法，并且GPR30具有PCA中的PRognostic值。提出了三个目的来检验这一假设。 目标1：在体外和体内环境下，确定GPR30在G-1诱导的AD和ADT抗PCA细胞中的作用。 目标2：确定DNA甲基化，组蛋白脱乙酰化或雄激素抑制是否参与了GPR30表达的调节，并比较了G-1的效率，单独或与其中一种药物在抑制PCA生长中的效率。 目标3：评估PCA中GPR30表达的预后价值。该项目将提供第一个支持GPR-30作为新型PCA治疗目标的证据，并为未来开发基于GPR30的PCA疗法的基础奠定了基础。 公共卫生相关性： 前列腺癌在一生中影响六分之一的男性，并对退伍军人的医疗保健产生重大影响。这项研究的主要目的是根据我们对G偶联蛋白受体GPR30的理解设计新的前列腺癌疗法。该研究与早期和晚期前列腺癌的治疗有关，并可能将GPR30建立为前列腺癌的预后标志。