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癌症特异性信号传导 通过该途径可以选择性地靶向人类肿瘤细胞。 的 蛋白酶体负责特异性降解蛋白质， 与细胞存活和凋亡密切相关，包括肿瘤 抑制性p53、细胞周期蛋白依赖性激酶抑制剂p27与细胞死亡 诱导剂Bax。我们发现蛋白酶体介导的Bax表达水平的增加 在晚期乳腺癌中，Bax蛋白的降解与Bax蛋白水平的降低密切相关。 人前列腺癌和用蛋白酶体治疗肿瘤细胞 抑制剂在线粒体中积累Bax蛋白，导致细胞色素c 释放、半胱天冬酶激活和凋亡。 我们还发现，酯 含键茶多酚能有效抑制肿瘤蛋白酶体活性 在体外（IC 50 86-194 nM）和体内（1-10 uM）， 喝绿色茶的人的血清。 蛋白酶体活性的抑制 在肿瘤细胞中导致几种天然蛋白酶体的积累， 底物，包括Bax。 基于这些结果，我们提出以下建议 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 例如Bax。 (2)酯键对蛋白酶体活性的抑制作用 含有茶多酚有助于预防前列腺癌， - 先前记载的绿色茶的抑制活性。 解决这些 根据这些假设，我们提出以下具体目标。 目标1：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物中。 目的2是评价效力， 茶多酚抑制蛋白酶体活性的选择性 前列腺癌细胞 目的3是探讨与 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 确定茶多酚的体内蛋白酶体抑制能力是否 用荷人前列腺的裸鼠研究其抗肿瘤活性 肿瘤的

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.