Inactivation of Id-1 in prostate cancer cells: A potential therapeutic target in inducing chemosensitization

Abstract

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 helix-loop-helix protein, is reported in several types of advanced cancers. It is suggested that high expression of Id-1 in cancer cells may provide an advantage for 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 chemotherapeutic drug-induced apoptosis in androgen- independent prostate cancer cells. Acknowledgements: This work was supported by RGC grants to X. H. Wang (HKU7478/03M) and Y. C. Wong (HKU 7314/01M and HKU7490/03M).