Regulation of the Response to Radiotherapy and Hyperthermia in Prostate Cancer by the 26s Proteasome.

摘要

The goal of the project was to evaluate the role of the proteasome in prostate cancer biology and response to heat and radiation therapy. We have shown considerable variation between prostate cancers in their functional proteasome activity. In all cases heat and radiation inhibit activity, and this is accompanied by changes in signal transduction pathways that are regulated through the proteasome. Most notably, NF-kappaB is suppressed by heat and by low radiation doses due to stabilization of IkappaBalpha. In contrast, at high radiation doses NF- kappaB is activated, even in the presence of IkappaBalpha stabilization, suggesting an alternative pathway of activation. The response of the proteasome to these stressors is very rapid, suggesting the proteasome regulates the initial cellular response to challenge. it is redox sensitive and radiation can directly affect proteasome activity, suggesting that it is a direct target for radiation. Interestingly, the 'immunoproteasome' containing interferon-inducible subunits appears to be most sensitive. We have shown that proteasome inhibitors cause apoptosis of prostate cancer cells and also sensitize them to the effects of radiation in vitro and in vivo. We have also identified the proteasome as a target for other drugs, such as anthracyclins and HIV protease inhibitors, suggesting that they might be used clinically in combination with radiation therapy to elicit improved therapeutic benefit.