ANTIAPOPTOTIC MECHANISMS IN PROSTATE CANCER

前列腺癌是最常见的恶性肿瘤，居第二位。 导致男性癌症死亡的原因。造成这一现象的原因之一 高死亡率是因为人类的前列腺癌是 对伽马辐射和化疗具有极强的抵抗力，这会导致 通过诱导细胞的凋亡。因此，恶性前列腺上皮 3年内复发，雄激素依赖且反复卧床不起 癌症。在这项提案中，我们确定了两种不同的细胞存活 雄激素依赖型和复发性前列腺癌所使用的途径。这个 CWR22人前列腺异种移植模型的建立 调控抗细胞凋亡途径的分子机制 让癌症卧床不起。在我们的初步数据中，我们证明 转录因子核因子-kappaB提供细胞存活提供细胞 前列腺细胞存活功能及显示核因子-kappaB活性 与核雄激素受体(AR)的表达相关。这些发现 是重要的，因为核因子-kappaB最近被证明能促进 癌基因通过抑制细胞凋亡而介导的肿瘤发生 复发性前列腺癌中核AR的存在可能是 在没有睾丸雄激素的情况下细胞存活。要了解 ，我们分析了前列腺癌复发的调控机制。 抗和促凋亡蛋白在雄激素非依赖性腺样囊性癌中的表达 CWR22R型号。与CWR22肿瘤相比，雄激素非依赖性CWR22R肿瘤 显示Bcl-2和c-Myc蛋白以及细胞质的升高 肿瘤抑制蛋白P53的定位。Bcl一2基因的上调 2在前列腺癌中的过度表达具有重要意义 已知的是，Bcl2能阻断雄激素诱导的细胞凋亡。这些 结果也很重要，因为Bcl-2和c-Myc癌蛋白通常 在人类前列腺癌中过表达，因为Bcl-2能够 通过与c-Myc协同作用克服p53依赖的细胞凋亡 亚细胞内将P53运输到细胞质。它的两个主要目标是 建议是：(1)确定核因子-kappaB的活性是否受 AR和确定核因子-kappaB是否提供抗凋亡细胞存活 在雄激素依赖型和复发性前列腺癌中的作用，以及 (2)阐明Bcl-2和c-Myc是否与雄激素相关。 前列腺癌的独立生长以及这是否涉及 P53肿瘤抑制蛋白失活。目标一号将决定 核因子-kappaB是否被AR信号激活 阻断诱导前列腺癌上皮细胞生长所必需的 细胞凋亡与使用核因子-kappaB抑制剂的联合治疗 化疗药物将改善前列腺癌的治疗。目标 2将使用特定的Bcl-2抑制剂来确定这是否 癌蛋白是雄激素非依赖性前列腺生存所必需的 癌症。目标3将确定是否需要c-Myc的表达 雄激素非依赖性肿瘤生长及c-Myc是否共表达 Bcl2通过胞浆途径失活P53 自动减支。这些研究对理解 调控异常的Bcl-2、c-Myc和核因子-kappaB在乳腺癌中的致癌作用 前列腺癌，并可能提出新的治疗方法。

Prostrate carcinoma is the most common malignancy and the second leading cause of cancer death among men. One of the contributing factors to this high mortality rate is due to the fact that human prostrate cancers are extremely resistant to gamma radiation and chemotherapies, which kill cells by the induction of apoptosis. Thus, malignant prostate epithelium relapse within 3 years with an androgen-dependent and recurrent prostrate cancer. In this proposal we have identified two distinct cell survival pathway utilized by androgen-dependent and recurrent prostate cancer. The CWR22 human prostate xenograft model will be used to understand the molecular mechanisms governing the anti-apoptotic pathways involved in prostrate cancer. In our preliminary data we demonstrate that the transcription factor NF-kappaB provides a cell survival provides a cell survival function in prostate cells and show that NF-kappaB activity correlates with nuclear androgen receptor (AR) expression. These findings are important because NF-kappaB has been recently demonstrated to promote oncogene-mediated tumorigenesis by inhibiting apoptosis and because the presence of nuclear AR in recurrent prostate cancer may be critical for cell survival in the absence of testicular androgens. To understand the mechanisms regulating recurrent prostate cancer, we analyzed the expression of anti-and pro-apoptotic proteins in the androgen-independent CWR22R model. Compared to CWR22 tumors, androgen-independent CWR22R tumors displayed elevated Bcl-2 and c-Myc proteins as well as cytoplasmic localization of the tumor suppressor protein p53. The upregulation of Bcl- 2 has significant implications in prostate cancer since the overexpression of Bcl-2 is known to block androgen ablation-induced apoptosis. These results are also important since Bcl-2 and c-Myc oncoproteins are commonly overexpressed in human prostatic carcinomas and because Bcl-2 is able to overcome p53-dependent apoptosis by cooperating with c-Myc to subcellularly traffic p53 to the cytoplasm. The two major goals of this proposal are to: (1) determine whether NF-kappaB activity is regulated by AR and determine if NF-kappaB provides an anti-apoptotic cell survival function in androgen-dependent as well as recurrent prostate cancer, and (2) elucidate whether Bcl-2 and c-Myc are associated with androgen- independent growth of prostate cancer and whether this involves the inactivation of the p53 tumor suppressor protein. Aim 1 will determine whether NF-kappaB is activated by AR-signaling, whether NF-kappaB is required for survival of prostate epithelium by blocking the induction of apoptosis and whether combined therapies employing NF-kappaB inhibitors and chemotherapeutic agents will improve therapy for prostate tumors. Aim 2 will employ specific inhibitors of Bcl-2 to determine whether this oncoprotein is required for the survival of androgen-independent prostate cancer. Aim 3 will determine whether the expression of c-Myc is required for androgen-independent tumor growth and whether co-expression of c-Myc and Bcl-2 results in the inactivation of p53 through cytoplasmic sequestration. These studies have important implications for understanding the oncogenic roles of dysregulated Bcl-2, c-Myc, and NF-kappaB in prostate cancer and may suggest novel approaches for treatment.