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.
| Kazi, Aslamuzzaman; Daniel, Kenyon G; Smith, David M et al. (2003) Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem Pharmacol 66:965-76 |
| Dou, Q Ping; Smith, David M; Daniel, Kenyon G et al. (2003) Interruption of tumor cell cycle progression through proteasome inhibition: implications for cancer therapy. Prog Cell Cycle Res 5:441-6 |
