APOPTOSIS IN PROSTATE CANCER

细胞凋亡是细胞程序性死亡的过程， 通过细胞表面作用的死亡因子配体触发的过程 受体，DNA损伤，细胞应激，或生长因子丢失 或激素刺激。 如果我们能激活细胞凋亡 在癌症治疗过程中，我们将通过以下方式提高治疗指数： 利用生理细胞信号通路，而不是 非特异性毒性损伤导致癌细胞死亡。 前列 在癌症治疗中，细胞凋亡的诱导是辐射的结果 和雄激素剥夺，最常用的治疗方法。 最近 临床结果表明，增加激素消融， 局部晚期前列腺癌的放射治疗 而不是单纯的放射治疗 这种有益的治疗效果可以 是由诱导不同的凋亡途径引起的， 增强细胞死亡。 DU-145前列腺癌细胞缺乏正常视网膜母细胞瘤（RB） 蛋白质，并且对辐射诱导的细胞凋亡具有高度抗性。 在DU-145细胞中恢复正常RB表达赋予了 对辐射和外源性C2- 神经酰胺 细胞凋亡是由丝氨酸蛋白酶介导的， 伴随着半胱天冬酶级联的激活。 RB介导的细胞凋亡 伴随着JUN表达的增加和 氨基末端JUN激酶（JNK）。 DU-145细胞提供了一个窗口 γ射线诱导的细胞死亡途径的研究。 我们假设RB介导了 识别DNA损伤并激活ABL激酶以触发 启动细胞死亡。 本提案的目的是阐明 RB介导的细胞凋亡新途径的细节， 导致丝氨酸蛋白酶的活化。 我们将描述 详细描述了由丝氨酸蛋白酶介导的细胞死亡应答， 与半胱天冬酶介导的死亡反应相比。 我们还将 用显性负性来测试我们假设的细胞死亡途径 突变体来阻断细胞死亡信号的关键步骤。 的 显性阴性构建体将阻断RB与ABL的相互作用，ABL 激酶、CAP激酶、SEK 1激酶和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.