Dissecting the role of G proteins in prostate cancer

描述（由申请人提供） 解剖G蛋白在前列腺癌中的体内作用：主要临床 晚期前列腺癌治疗的局限性是 前列腺肿瘤到雄激素非依赖状态，其中雄激素消融治疗 变得无效。前列腺癌的早期症状有哪些？ 雄激素不依赖性没有明确的定义，虽然肽生长 作用于其同源受体酪氨酸激酶的因子， 牵连最近的研究进展表明，癌症的转变 雄激素非依赖状态与某些G 蛋白偶联受体和/或其配体。在体外，脂质和 肽类生长因子通过解离途径刺激前列腺细胞生长 异源三聚体G蛋白α（G-α）和/或β γ（G-β γ） 亚基对刺激其相关的G蛋白偶联 受体。特别是，G蛋白的两个亚家族（Gq和Gi）似乎 在前列腺细胞的病理生长中起关键作用。具体 Gq（G-α-qct）和G-β γ（GRK 2ct）信号传导的肽抑制剂具有 最近被开发出来，可能代表了一种新的治疗机会， 成功治疗前列腺癌这个问题的核心假设是 G蛋白是病理性生长的关键调节因子， 前列腺癌和Gq和G-β γ的靶向抑制 信号传导将限制前列腺的致瘤生长。在体外和 包括小鼠异种移植物模型的体内模型系统是可用的， 用来检验这个假设。为了在大肠杆菌中表达G-α-qct和GRK 2ct肽， 在培养和体内的前列腺癌细胞中，我们将利用腺病毒 向量。具体目的是：（1）确定Gq的具体作用， G-β-gamma（通过使用G-α-qct和GRK 2ct）在ERK激活和前列腺 使用体外模型系统的细胞生长和迁移;（2）为了确定 G-α-q和G-β，γ亚基相互作用的分子机制， 前列腺癌细胞中的表皮生长因子受体;和（3） 确定Gq和G-β γ亚基在体内生长中的作用， 前列腺肿瘤的动物模型系统。这些活动的圆满结束 研究可能将G-α-qct和/或GRK 2ct确定为新的分子基因疗法 有效治疗前列腺癌的方式。

DESCRIPTION (Provided by the applicant) Dissecting The In vivo Role Of G Proteins In Prostate Cancer: Major clinical limitations in the treatment of advanced prostate cancer is transition of the prostate tumor to androgen-independent state, where androgen ablation therapy becomes ineffective. Factors involved in the transition of the prostate cancer to androgen-independence are not clearly defined, although peptide growth factors, which act upon their cognate receptor tyrosine kinases, have been implicated. Recent research advances demonstrate that transition of the cancer to androgen-independent state is associated with increased expression of some G protein-coupled receptors and/or their ligands. In vitro, both lipid and peptide growth factors stimulate prostate cell growth via dissociated heterotrimeric G proteins alpha(G-alpha) and/or beta gamma (G-beta gamma) subunits in response to stimulation of their associated G protein-coupled receptors. In particular, two subfamilies of G proteins (Gq and Gi) appear to play critical roles in the pathological growth of prostate cells. Specific peptide inhibitors of Gq (G-alpha-qct) and G-beta gamma (GRK2ct) signaling have recently been developed and may represent a novel therapeutic opportunity for the successful treatment of prostate cancer. The central hypothesis of this proposal is that G proteins are critical regulators of pathological growth of prostate cancer and that the targeted inhibition of Gq and G-beta gamma signaling will limit tumorigenic growth of the prostate. Both in vitro and in vivo model systems, including a mouse xenograft model, are available and will be used to test this hypothesis. To express G-alpha-qct and GRK2ct peptides in prostate cancer cells in culture and in vivo, we will utilize adenoviral vectors. The specific aims are: (1) To determine the specific role of Gq and G-beta gamma (by using G-alpha-qct and GRK2ct) in ERK activation and prostate cell growth and migration using in vitro model systems; ( 2) To determine the molecular mechanisms by which G-alpha-q and G-beta,gamma subunits crosstalk to epidermal growth factor receptor in prostate cancer cells; and ( 3) To determine the role of Gq and G-beta gamma subunits in the in vivo growth of prostate tumors using animal model systems. The successful conclusion of these studies may identify G-alpha-qct and/or GRK2ct as novel molecular gene therapy modalities effective for the treatment of prostate cancer.