APOPTOSIS IN PROSTATE CANCER

细胞凋亡，即细胞程序性死亡的过程，是一种生理过程。 死亡因子配体作用于细胞表面引发的过程 受体，DNA损伤，细胞压力，或生长因子的丧失 或者荷尔蒙刺激。如果我们能实现细胞凋亡的激活 在癌症治疗期间，我们将通过以下方式来提高治疗指数 利用生理细胞信号通路而不是 非特异性毒物侮辱导致癌细胞死亡。在前列腺中 癌症治疗中，诱导细胞凋亡既是辐射的结果 和雄激素剥夺，这是最常用的治疗方法。近期 临床结果表明，激素消融增加了对 局部晚期前列腺癌放射治疗延长生存期 仅仅是为了接受放射治疗。这种有益的治疗效果可能 是通过诱导不同的细胞凋亡途径产生的 增强了细胞死亡。 正常视网膜母细胞瘤DU-145前列腺癌细胞缺失 蛋白质，并高度抵抗辐射诱导的细胞凋亡。 恢复DU-145细胞Rb的正常表达 辐射和外源性C2-2诱导细胞凋亡的能力 神经酰胺。细胞凋亡是由丝氨酸蛋白酶介导的，而不是 伴随着caspase级联的激活。Rb介导的细胞凋亡 伴随着Jun表达的增加和细胞的激活 氨基末端Jun激酶(JNK)。DU-145电池提供了一个窗口 伽玛射线诱导的一种特定细胞死亡途径的研究。 我们假设RB在两个基因之间起关键作用 识别DNA损伤和激活ABL激酶以触发 启动细胞死亡。这项提议的目的是澄清 Rb和Rb介导的细胞凋亡新途径的细节 导致丝氨酸蛋白酶的激活。我们将描述 详细地说，丝氨酸蛋白酶和丝氨酸蛋白酶介导的细胞死亡反应 将其与半胱氨酸天冬氨酸酶介导的死亡反应进行比较。我们还将 使用显性负值测试细胞死亡的假设路径 突变体可以阻断细胞死亡信号中的关键步骤。这个 显性否定结构将阻止RB与ABL、ABL 激酶、CAP、SEK1和Jun。

Apoptosis, the process of programmed cell death, is a physiologic process triggered by death factor ligands acting through cell surface receptors, by DNA damage, by cell stress, or by loss of growth factor or hormone stimulation. If we could achieve activation of apoptosis during cancer treatment, then we would improve the therapeutic index by exploiting physiologic cellular signaling pathways rather than nonspecific toxic insults to cause cancer cell death. In prostate cancer treatment, induction of apoptosis is the result of both radiation and androgen deprivation, the most commonly used therapies. Recent clinical results have shown that the addition of hormone ablation to radiation therapy for locally advanced prostate cancer prolongs survival over radiation therapy alone. This beneficial therapeutic effect may have resulted from the induction of separate apoptosis pathways that enhanced cell death. DU-145 prostate cancer cells are deficient in normal retinoblastoma (RB) protein and are highly resistant to radiation-induced apoptosis. Restoration of normal RB expression in DU-145 cells conferred the ability to undergo apoptosis in response to radiation and exogenous C2- ceramide. Apoptosis was mediated by serine proteases and was not accompanied by activation of the caspase cascade. RB-mediated apoptosis was accompanied by increased expression of JUN and activation of the amino terminal JUN kinase (JNK). DU-145 cells provide a window to the study of a specific cell death pathway induced by gamma-irradiation. We have hypothesized that RB mediates a critical link between recognition of DNA damage and activation of ABL kinase to trigger the initiation of cell death. The aims of this proposal are to elucidate the details of the novel pathway for apoptosis mediated by RB and resulting in the activation of serine proteases. We will characterize in detail the cell death response mediated by serine proteases and compare it to the death response mediated by caspases. We will also test our hypothetical pathway for cell death using dominant negative mutants to block critical steps in the cell death signaling. The dominant negative constructs will block RB interaction with ABL, ABL kinase, CAP kinase, SEK1 kinase and JUN.