G Protein-Dependent Growth of Prostate Cancer

癌症是由控制细胞生长和细胞死亡的信号通路失调引起的。 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。 尽管雄激素和肽类生长因子与前列腺良性和恶性生长的启动和/或进展有关，但对这些因子的了解仍然很少。 我们最近的研究结果支持了G蛋白促进前列腺肿瘤生长和转移的新假设，即溶血磷脂酸（LPA）的G蛋白偶联受体的激活导致培养的前列腺癌细胞的有丝分裂信号、生长和侵袭增加，以及表皮生长因子和雄激素受体的反式激活。 进一步支持这一假设的是发现百日咳毒素，一种Gi/o蛋白的药理学抑制剂，抑制注射到裸鼠中的前列腺癌PC-3细胞的生长和转移。虽然G蛋白参与前列腺癌细胞的生长和转移，但其机制尚不清楚。 该提议的中心假设是LPA激活了介导前列腺癌细胞中生长和转移信号转导的G蛋白库。实验将主要集中在前列腺癌细胞中LPA介导的促有丝分裂信号转导途径的生物化学和药理学特性上。 具体目标是：[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]鉴定Ga和G β亚基在前列腺癌细胞中LPA调节的ERK和雄激素受体活化中的特定作用。 这些拟议研究的成功结论将为合理开发控制人类前列腺癌的新的有效策略提供所需的信息。

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.