G Protein-Dependent Growth of Prostate Cancer

前列腺癌的 G 蛋白依赖性生长

• 批准号: 6778240
• 负责人: Yehia Daaka
• 金额: $ 23.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778240
• 关键词: G protein; androgen receptor; athymic mouse; benign prostate hyperplasia; biological signal transduction; cell growth regulation; cell motility; cell proliferation; cellular pathology; chimeric proteins; enzyme linked immunosorbent assay; male; metastasis; mitogen activated protein kinase; mitogens; neoplastic growth; pathologic process; phosphatidate; posttranslational modifications; prostate; prostate neoplasms; protein structure function; receptor expression; tissue /cell culture; transfection

Cancer results from the disregulation of signaling pathways that control cell growth and cell death. Prostate diseases, including benign prostate hyperplasia and prostate cancer, are the leading malignancies affecting males in the United States and abroad. Factors responsible for the initiation and/or progression of both benign and malignant growth of the prostate remain poorly understood, although androgens and peptide growth factors have been implicated. The novel hypothesis that G proteins contribute to the neoplastic growth and metastasis of the prostate is supported by our recent findings that activation of G protein-coupled receptors for lysophosphatidic acid (LPA) results in increased mitogenic signaling, growth and invasion of cultured prostate cancer cells, and transactivation of the epidermal growth factor and androgen receptors. Further support to this hypothesis is the finding that pertussis toxin, a pharmacologic inhibitor of Gi/o proteins, inhibits the growth and metastasis of prostate cancer PC-3 cells injected into nude mice. Although clearly involved, the mechanisms by which G proteins contribute to growth and metastasis of prostate cancer cells are not known. The central hypothesis of this proposal is that LPA activates a pool of G proteins that mediate the transduction of growth and metastatic signals in prostate cancer cells. Experiments will focus principally on the biochemical and pharmacological properties of LPA-mediated mitogenic signal transduction pathways in prostate cancer cells. The specific aims are: [1] To determine the effect of LPA stimulation on prostate cell growth and motility using in vitro model systems; [2] To determine the role of specific LPA receptor subtypes in the growth and motility of prostate cells; [3] To identify the specific role of Galpha and Gbetagamma subunits in the LPA- regulated activation of ERK and androgen receptor in prostate cancer cells. The successful conclusion of these proposed studies will provide needed information to rationally develop novel and effective strategies for the control of prostate cancer in humans.

癌症是由于无法控制细胞生长和细胞死亡的信号通路而导致的。 前列腺疾病，包括良性前列腺增生和前列腺癌，是影响美国和国外男性的主要恶性肿瘤。 尽管已经涉及雄激素和肽生长因子，但导致前列腺良性和恶性增长的启动和/或进展的因素仍然很差。 我们最近的发现支持了G蛋白有助于前列腺的肿瘤生长和转移的新假设，即我们最近的发现，即G蛋白偶联受体的激活受体（LPA）会导致有丝分裂信号传导，培养的前列腺癌细胞的生长和侵袭的生长以及培养的前列腺癌的生长因子，以及培养的生长因子的增长。 对这一假设的进一步支持是，GI/O蛋白的药物抑制剂百日咳毒素抑制了注射到​​裸鼠中的前列腺癌PC-3细胞的生长和转移。尽管显然涉及，但G蛋白促进前列腺癌细胞的生长和转移的机制尚不清楚。 该提案的中心假设是LPA激活了介导前列腺癌细胞生长和转移信号转导的G蛋白池。实验将主要集中于前列腺癌细胞中LPA介导的有丝分裂信号转导途径的生化和药理特性。 具体目的是：[1]使用体外模型系统确定LPA刺激对前列腺细胞生长和运动的影响； [2]确定特定LPA受体亚型在前列腺细胞生长和运动中的作用； [3]确定Galpha和Gbetagamma亚基在前列腺癌细胞中ERK和雄激素受体的LPA调节激活中的特定作用。 这些提出的研究的成功结论将提供所需的信息，以合理地制定新的有效策略来控制人类前列腺癌。