Inactivation of Id-1 in prostate cancer cells: A potential therapeutic target in inducing chemosensitization to taxol through activation of JNK pathway.
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, by using RNA interfering technology, we inactivated the Id-1 gene in 2 androgen-independent prostate cancer cell lines, DU145 and PC3, and investigated whether downregulation of Id-1 could lead to increased sensitivity to a commonly used anticancer drug, taxol. By using colony forming assay and MTT assay, 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, which is 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.
Zhang
Xiaomeng
X
Cancer Biology Group, Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong.
Ling
Ming-Tat
MT
Wang
Xianghong
X
Wong
Y C
YC
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis* / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D034622:RNA Interference; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000972:Antineoplastic Agents, Phytogenic; D051798:Inhibitor of Differentiation Protein 1; D048670:MAP Kinase Kinase 4; D017239:Paclitaxel