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 治疗很少是治愈性的，因为个体内的癌症 患者含有雄激素依赖性和非依赖性细胞。 几项研究表明抗凋亡蛋白的增加 Bcl-2在非肿瘤依赖性复发性前列腺癌中的作用， 前列腺癌细胞群可能在雄激素作用后抵抗凋亡， 由于Bcl-2蛋白的表达而退出。 方法来识别 因此，治疗复发性前列腺癌的新方法应该 包括制定各种战略，使之能够降低- Bcl-2表达的调控。 我们最近的研究发现， 一种新的促凋亡蛋白--前列腺凋亡反应-4 （Par-4），其可敏化雄激素依赖性和非依赖性的 细胞凋亡。 最重要的是，我们的初步研究表明 Par-4下调Bcl-2蛋白表达。 这个目标 本课题旨在了解Par-4和Bcl-2之间的关系 在雄激素依赖性和非依赖性前列腺癌细胞中的表达 线，并在肿瘤标本代表原发性，转移性，或 复发性前列腺癌 该项目提出了三个具体目标。 我将向 Par-4下调Bcl-2的机制。具体来说，我们将 测试Par-4是否引起bcl-2的转录抑制 启动子;如果是，进一步鉴定bcl-2中的顺式元件 启动子介导的抑制。目标二将审查功能 Par-4介导bcl-2下调与前列腺癌的相关性 细胞 最后，目标III将解决Par-4和Bcl-2的表达 在前列腺依赖性和非依赖性前列腺癌标本中， 患者 我们将使用定性和定量方法， 确定Par-4和Bcl-2的表达是否与 晚期、转移性或复发性前列腺肿瘤。 所有这些 研究将使我们能够检查亲， 凋亡蛋白Par-4和关键细胞存活蛋白Bcl-2， 设计控制复发性前列腺肿瘤的策略。 因为 Bcl-2阻断多种胰岛素诱导的凋亡途径， 这项研究的结果表明， 可以扩展到促进不同癌症中的Par-4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.