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

基本信息

批准号：
8397551
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
项目类别：
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/8397551
关键词：
5&apos 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 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 prostate cancer cell quinoline receptor research study response small hairpin RNA therapeutic target therapy resistant trend tumor growth urologic

项目摘要

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.

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，并且随着人口老龄化，其发病率将继续上升。尽管前列腺癌疗法的开发不断取得进展，但患有雄激素剥夺疗法（ADT）耐药疾病的患者的选择有限。近年来，具有降低心血管毒性的肠外雌激素在 PCa 治疗中显示出了良好的前景。在质膜和内质网均鉴定出一种孤儿 G 蛋白偶联受体 (GPR30)，该受体与雌激素具有高亲和力和低容量结合能力。该受体被认为是雌激素非基因组作用的关键介质。与配体结合后，GPR30 以不依赖于 ER 的细胞类型特异性方式刺激或抑制细胞增殖。 G-1(1-[4-(6-溴苯并[1,3]二氧杂环戊烯-5基)-3a,4,5,9b-四氢-3H-环戊[c]喹啉-8-基]-乙酮的鉴定）作为一种没有雌激素活性的 GPR30 选择性激动剂，为阐明 GPR30 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 GPR30 的细胞中ER1 和/或 ER2。使用G-1，并通过siRNA敲低实验证实，我们最近证明了G-1对培养的AD和ADT耐药PCa细胞的生长具有强大的抑制作用。它还抑制裸鼠体内 PC-3 异种移植物的生长。与邻近正常组织相比，在 PCa 临床标本中观察到 GPR30 mRNA 表达减少的趋势，尽管 PCa 标本之间的表达程度差异很大。用 5-aza-2'-脱氧胞苷、去甲基化剂、tricostatinA、HDACi 或 ADT 处理 PCa 细胞会增加 GPR30 表达。基于这些新发现，我们假设通过其特异性配体 G-1 激活 GPR30 信号传导，无论是单独使用还是与去甲基化剂、组蛋白脱乙酰酶抑制剂 (HDACi) 或雄激素消除联合使用，都是一种有效的抗 PCa 药物治疗，并且 GPR30 对 PCa 具有预后价值。提出了三个目标来检验这一假设。目标 1：在体外和体内环境下，确定 GPR30 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 2：确定 DNA 甲基化、组蛋白脱乙酰化或雄激素抑制是否参与 GPR30 表达的调节，并比较 G-1 单独使用或与其中一种药物联合使用在抑制 PCa 生长方面的功效。目标 3：评估 PCa 中 GPR30 表达的预后价值。该项目将为GPR-30作为前列腺癌新治疗靶点提供首个证据，并为未来开发基于GPR30的前列腺癌疗法奠定基础。