Abstract
1265
Resistance to anticancer drugs is the major problem in the treatment of many advanced cancers including androgen-independent prostate cancer. Recently, increased expression of Id-1, a basic helix-loop-helix protein, is reported in several types of advanced cancer. It is suggested that high expression of Id-1 may provide an advantage for cancer cell survival and inactivation of Id-1 may be able to increase cancer cells’ susceptibility to apoptosis. To test this hypothesis, in this study, using RNA interfering technology, we inactivated the Id-1 gene in two androgen-independent prostate cancer cell lines, DU145 and PC3, and investigated if downregulation of Id-1 could lead to increased sensitivity to a commonly used anticancer drug, taxol. Using colony forming and MTT assays, we found that inactivation of Id-1 resulted in both decreased colony forming ability and cell viability in prostate cancer cells after taxol treatment. In addition, the si-Id-1 induced sensitization to taxol was associated with activation of apoptosis pathway demonstrated by increased apoptotic index, DNA laddering, sub-G1 phase of the cell cycle, as well as cleaved-PARP and Caspase 3. Furthermore, c-Jun N-terminal kinase (JNK), one of the common pathways responsible for taxol-induced apoptosis, was also activated in the si-Id-1 transfected cells. Inhibition of JNK activity by a specific inhibitor, SP600125, blocked the si-Id-1-induced sensitivity to taxol. These results indicate that increased Id-1 expression in prostate cancer cells may play a protective role against apoptosis, and downregulation of Id-1 may be a potential target to increase sensitivity of taxol-induced apoptosis in prostate cancer cells.(Supported by RGC grants:HKU7314/01M, hku7490/03M, HKU7470/04M, HKU7478/03M)
- American Association for Cancer Research