TEA TARGETING PROTEASOME--A ROLE IN CANCER PREVENTION

描述(由申请人提供)： 我们的长期目标是找到一种癌症特异性的信号转导 选择性靶向人类肿瘤细胞的途径。这个 蛋白酶体负责蛋白质的特定降解 与细胞存活和凋亡密切相关，包括肿瘤 抑制子P53、细胞周期蛋白依赖性激酶抑制物P27与细胞死亡 诱导剂巴克斯。我们已经发现，蛋白酶体介导的Bax水平增加 进展期BAX蛋白水平下降与降解密切相关 人前列腺癌与蛋白酶体治疗肿瘤细胞 抑制物在线粒体中积累Bax蛋白，导致细胞色素c 释放、半胱氨酸天冬氨酸酶激活和细胞凋亡。我们还发现了这种酯 含键茶多酚对肿瘤蛋白酶体活性的抑制作用 体外(IC_(50)86-194 nm)和体内(1-10微米) 绿茶饮用者的血清。这种对蛋白酶体活性的抑制 在肿瘤细胞中导致几种蛋白酶体的天然积聚 底物，包括Bax。基于这些结果，我们提出如下建议 两个假设。(1)前列腺癌的危险因素之一是 选择性降解生长抑制蛋白的蛋白酶体活性 比如BAX。(2)酯键对蛋白酶体活性的抑制作用 含有茶多酚有助于前列腺癌的预防和 -先前记录的绿茶的抑制活性。要解决这些问题 根据假设，我们提出了以下具体目标。目标1是评估 茶多酚抑制蛋白酶体活性的效力和选择性 在前列腺癌细胞提取液中。目标2是评估效力和 茶多酚对正常组织蛋白酶体活性的选择性抑制作用 前列腺癌细胞。目标3是调查两个人之间的关系 茶多酚对蛋白酶体介导的Bax的抑制作用 降解并诱导前列腺癌细胞死亡。未来的目标是 茶多酚体内蛋白酶体抑制能力的测定 它们在荷人前列腺癌裸鼠体内的抗肿瘤活性 肿瘤。

DESCRIPTION (provided by applicant): Our long-term objective is to find a cancer-specific signal transduction pathway via which human tumor cells can be selectively targeted. The proteasome is responsible for the specific degradation of proteins that are intimately involved in cell survival and apoptosis, including the tumor suppressor p53, the cyclin-dependent kinase inhibitor p27 and the cell death inducer Bax. We have found that increased levels of proteasome-mediated Bax degradation correlate well with decreased levels of Bax protein in advanced human prostate cancer and that treatment of tumor cells with a proteasome inhibitor accumulates Bax protein in the mitochondria, leading to cytochrome c release, caspase activation and apoptosis. We have also found that ester bond-containing tea polyphenols potently inhibit the tumor proteasome activity in vitro (IC50 86-194 nM) and in vivo (1-10 uM) at the concentrations found in the serum of green tea drinkers. This inhibition of the proteasome activity in tumor cells results in accumulation of several proteasome natural substrates, including Bax. Based on these results, we propose the following two Hypotheses. (1) One of prostate cancer risk factors is increased level of the proteasomal activity that selectively degrades growth suppressor proteins such as Bax. (2) Inhibition of the proteasome activity by ester bond- containing tea polyphenols contributes to the prostate cancer-preventative and -inhibitory activities of green tea documented previously. To address these hypotheses, we propose the following Specific Aims. Aim 1 is to evaluate potency and selectivity of tea polyphenols to inhibit the proteasome activity in prostate cancer cell extracts. Aim 2 is to evaluate potency and selectivity of tea polyphenols to inhibit the proteasome activity in intact prostate cancer cells. Aim 3 is to investigate the relationship between the abilities of tea polyphenols to inhibit the proteasome-mediated Bax degradation and to induce prostate cancer cell death. A Future Aim is to determine whether in vivo proteasome-inhibitory ability of tea polyphenols is related to their antitumor activity using nude mice bearing human prostate tumors.