Metabotropic Glutamate Receptor 1 in African American Prostate Cancer

非裔美国人前列腺癌中的代谢型谷氨酸受体 1

• 批准号: 8829801
• 负责人: SHAHRIAR KOOCHEKPOUR
• 金额: $ 18.47万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829801
• 关键词: African American; Age; Apoptosis; Benign; Biochemical; Bioenergetics; Biological; Biological Factors; Brain; Breast Melanoma; Cancer Biology; Cancer Cell Growth; Cancer Patient; Caucasians; Cell Line; Cell Proliferation; Citric Acid Cycle; Clinical; Data; Development; Diagnostic; Environment; Epithelial Cells; Ethnic Origin; Family; GRM1 gene; Genetic; Gland; Gleason Grade for Prostate Cancer; Glutamate Receptor; Glutamates; Growth; Health; Health Services Accessibility; Healthcare Systems; In Vitro; Incidence; Indolent; Investigation; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metabolic; Metabotropic Glutamate Receptors; Molecular Target; Multivariate Analysis; Neoplasm Metastasis; Non-Essential Amino Acid; Oncogenic; Outcome; Patients; Penetrance; Phenotype; Play; Proliferating; Prostate; Prostate Cancer therapy; Prostate-Specific Antigen; Race; Radical Prostatectomy; Recurrence; Resistance; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Staining method; Stains; System; TNM; Testing; Time; Tissues; Transgenic Mice; Tumor Volume; Xenograft Model; base; burden of illness; cancer cell; cancer health disparity; caucasian American; cell motility; clinically significant; deprivation; ethnic difference; lipid biosynthesis; melanocyte; melanoma; member; men; metabotropic glutamate receptor type 1; migration; mortality; novel; outcome forecast; overexpression; prognostic; prostate cancer cell; prostate cancer cell line; racial difference; racial disparity; subcutaneous; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Prostate cancer (PCa) presents with the greatest racial disparity of any cancer in the U.S., with an alarmingly high incidence and mortality rate among African Americans (AAs). AA men with PCa present with higher tumor volume, more advanced stage, higher Gleason grade, higher prostate-specific antigen (PSA), and worse prognosis than Caucasian Americans (CAs). The underlying reasons for such disproportionate ethnic differences may reflect genuine racial differences in cancer biology, socio-cultural differences, or access to health care systems. Recently, we discovered that serum glutamate levels positively correlate with PCa aggressiveness and Gleason score (e8 versus d6) in AAs and CAs. However, glutamate levels were higher in AAs, with primary or metastatic castrate-resistant (CR) PCa than in CAs. Glutamate deprivation or blockade with a glutamate receptor (i.e., GRM1) antagonist significantly decreased growth, migration and invasion and induced apoptosis in PCa cells. We also demonstrated a higher GRM1 expression in MDA-PCa2b (metastatic AA-PCa cell line) than in the E006AA (primary AA-PCa cell line). GRM1 overexpression increased E006AA cell proliferation, migration, and invasion. Our preliminary data show that GRM1 expression is higher in PCa tissues than in normal or benign glands in AAs. Based on these data, we hypothesized that GRM1 expression levels contribute to biological and clinical aggressiveness of PCa in AAs. Our hypothesis will be tested in the following Specific Aims: (1) to determine the association between tissue expression of GRM1 and clinicohistopathological predictors or prognosticators of PCa progression or aggressiveness in AAs; and (2) to determine the association between GRM1 expression levels and invasive and metastatic phenotypes in AA-PCa cells. Data generated from this exploratory study will define biological and/or clinicohistopathological significance or relevance of GRM1 expression in AA-PCa and may prove useful in discriminating clinically or biologically aggressive tumors from indolent (non-aggressive) tumors and minimizing PCa disparity in AAs.

描述（由申请人提供）：前列腺癌 (PCa) 是美国所有癌症中种族差异最大的一种，在非裔美国人 (AA) 中发病率和死亡率高得惊人。与白人美国人 (CA) 相比，患有 PCa 的 AA 男性肿瘤体积更大、分期更晚、格里森分级更高、前列腺特异性抗原 (PSA) 更高且预后更差。这种不成比例的种族差异的根本原因可能反映了癌症生物学、社会文化差异或获得医疗保健系统的真正种族差异。 最近，我们发现血清谷氨酸水平与 AA 和 CA 中 PCa 侵袭性和格里森评分（e8 与 d6）呈正相关。然而，原发性或转移性去势抵抗 (CR) PCa 的 AA 中谷氨酸水平高于 CA。谷氨酸剥夺或用谷氨酸受体（即 GRM1）拮抗剂阻断可显着降低 PCa 细胞的生长、迁移和侵袭并诱导细胞凋亡。我们还证明 MDA-PCa2b（转移性 AA-PCa 细胞系）中的 GRM1 表达高于 E006AA（原发性 AA-PCa 细胞系）。 GRM1 过表达增加 E006AA 细胞增殖、迁移和侵袭。我们的初步数据表明，PCa 组织中的 GRM1 表达高于 AA 中的正常或良性腺体。 基于这些数据，我们假设 GRM1 表达水平有助于 AA 中 PCa 的生物学和临床侵袭性。我们的假设将在以下具体目标中得到检验：（1）确定 GRM1 的组织表达与 PCa 进展或 AA 侵袭性的临床组织病理学预测因子或预后因子之间的关联； (2) 确定 AA-PCa 细胞中 GRM1 表达水平与侵袭性和转移性表型之间的关联。 这项探索性研究产生的数据将定义 AA-PCa 中 GRM1 表达的生物学和/或临床组织病理学意义或相关性，并可能有助于区分临床或生物学侵袭性肿瘤与惰性（非侵袭性）肿瘤，并最大限度地减少 AA 中 PCa 的差异。

项目成果

Therapeutic Rationales, Progresses, Failures, and Future Directions for Advanced Prostate Cancer.

• DOI: 10.7150/ijbs.14090
• 发表时间: 2016
• 期刊: International journal of biological sciences
• 影响因子: 9.2
• 作者: Wadosky KM;Koochekpour S
• 通讯作者: Koochekpour S

Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer.

• DOI: 10.18632/oncotarget.10901
• 发表时间: 2016-09-27
• 期刊: Oncotarget
• 作者: Wadosky KM;Koochekpour S
• 通讯作者: Koochekpour S

GRM1 is An Androgen-Regulated Gene and its Expression Correlates with Prostate Cancer Progression in Pre-Clinical Models.

GRM1 是一种雄激素调节基因，其表达与临床前模型中前列腺癌的进展相关。

• DOI: 10.1158/1078-0432.ccr-16-0137
• 发表时间: 2016
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Shourideh,Mojgan;Azabdaftari,Gissou;Attwood,Kristopher;DePriest,Adam;Wadosky,KristineM;Gillard,BryanM;Karasik,Ellen;Heemers,Hannelore;Kyprianou,Natasha;Gelman,IrwinH;Corey,Eva;Vessella,RobertL;Mohler,JamesL;Koochekpour,Shah
• 通讯作者: Koochekpour,Shah