APOPTOSIS SPECIFIC GENES IN PROSTATE CARCINOMA CELLS

雄激素消融术是前列腺癌的标准治疗方法，但这 治疗很少能治愈，因为一个人体内的癌症 患者体内既有雄激素依赖性细胞，也有非雄激素依赖性细胞。 多项研究表明，抗凋亡蛋白的含量增加。 Bcl2在激素非依赖性复发性前列腺癌中的表达，并提示 前列腺癌细胞群在雄激素作用后可能抵抗细胞凋亡 Bc l-2蛋白表达导致戒断。确定以下目标的方法 因此，治疗复发性前列腺癌的新疗法应该 包括制定各种战略，以使下降- Bcl2基因表达的调控。我们最近的研究发现， 一种新的促凋亡蛋白命名为前列腺细胞凋亡反应-4 (PAR-4)对雄激素依赖和非雄激素依赖均有增敏作用 使细胞发生凋亡。最重要的是，我们的初步研究表明 PAR-4下调Bc l-2蛋白表达。这是一个目标 项目是了解PAR-4和Bcl2之间的关系 雄激素依赖和非雄激素依赖性前列腺癌细胞的表达 在代表原发的、转移的或 复发性前列腺癌。 本项目提出了三个具体目标。Aim我将发表演讲 PAR-4下调Bc l-2表达的机制具体来说，我们将 检测PAR-4是否导致bc1-2转录抑制 启动子；如果是，进一步鉴定bc1-2中的顺式元件 调停压制的推动者。AIM II将检查功能 PAR-4介导的bcl2下调与前列腺癌的关系 细胞。最后，Aim III将解决PAR-4和Bcl-2的表达问题 在激素依赖和非激素依赖的前列腺癌样本中 病人。我们将使用定性和定量的方法来 确定PAR-4和Bc l-2的表达是否呈负相关 晚期、转移性或复发性前列腺癌。加在一起，这些 研究将使我们能够研究PRO和PRO之间的功能联系 凋亡蛋白PAR-4和关键细胞生存蛋白Bcl-2，以及帮助 设计控制复发前列腺癌的策略。因为 BCL-2阻断多种损伤诱导的细胞凋亡通路，从而 这项研究的发现使人对抗癌治疗产生抵抗力 可以扩展以促进PAR-4在不同癌症中的凋亡 模型系统。

Androgen-ablation is standard therapy for prostate cancer, but this therapy is rarely curative because the cancer within an individual patient contains both androgen-dependent and - independent cells. Several studies have shown an increase in the anti-apoptotic protein Bcl-2 in hormone-independent recurrent prostate cancer, and suggested that groups of prostate cancer cells may resist apoptosis after androgen withdrawal owing to expression of Bcl-2 protein. Approaches to identify novel treatments for recurrent prostate cancer, therefore, should include the development of various strategies that will enable down- regulation of Bcl-2 expression. Our recent studies have identified a novel pro-apoptotic protein designated Prostate Apoptosis Response-4 (Par-4) that can sensitize both androgen-dependent and -independent cells to apoptosis. Most importantly, our preliminary studies suggest that Par-4 down-regulates Bcl-2 protein expression. A goal of this project is to understand the relationship between Par-4 and Bcl-2 expression in androgen-dependent and -independent prostate cancer cell lines, and in tumor specimens representing primary, metastatic, or recurrent prostate cancers. Three specific aims are proposed in this project. Aim I will address the mechanism by which Par-4 down-regulates Bcl-2. Specifically, we will test whether Par-4 causes transcriptional repression of the bcl-2 promoter; and if so, further identify the cis elements in the bcl-2 promoter that mediate the repression. Aim II will examine the functional relevance of Par-4 mediated bcl-2-down-regulation in prostate cancer cells. Finally, Aim III will address the expression of Par-4 and Bcl-2 in hormone-dependent and -independent prostate cancer specimens from patients. We will use qualitative and quantitative approaches to determine whether Par-4 and Bcl-2 expression is inversely related in advanced, metastatic, or recurrent prostate tumors. Together, these studies will enable us to examine the functional link between the pro- apoptotic protein Par-4 and a key cell survival protein Bcl-2, and help design strategies for control of recurrent prostate tumors. Because Bcl-2 blocks diverse insult-induced apoptotic pathways and thereby confers resistance to anti-cancer therapy, the findings of this study can be extended to facilitate apoptosis with Par-4 in diverse cancer model systems.