Abstract
The growth-promoting effect of Id-1 (inhibitor of differentiation/DNA binding) has been demonstrated in a number of human cancers. However, the mechanisms responsible for its action are not clear. In this study, we report that in prostate cancer cells, Id-1 promotes cell survival through activation of nuclear factor-κB (NF-κB) signalling pathway. After stable expression of Id-1 protein in LNCaP cells, we found that the Id-1 transfectants showed increased resistance to apoptosis induced by TNFα through inactivation of Bax and caspase 3. In addition, in the LNCaP cells expressing ectopic Id-1 protein, we also observed increased NF-κB transactivation activity and nuclear translocation of the p65 and p50 proteins, which was accompanied by upregulation of their downstream effectors Bcl-xL and ICAM-1. These results indicate that the Id-1-induced antiapoptotic effect may be via NF-κB signalling transduction pathway in these cells. In addition, inactivation of Id-1 by its antisense oligonucleotide and retroviral construct in DU145 cells resulted in the decrease of nuclear level of p65 and p50 proteins, which was associated with increased sensitivity to TNFα-induced apoptosis. Our results strongly suggest that Id-1 may be one of the upstream regulators of NF-κB and activation of NF-κB signalling pathway may be essential for Id-1 induced cell proliferation through protection against apoptosis. Our findings also suggest a potential therapeutic strategy in which inactivation of Id-1 may lead to sensitization of prostate cancer cells to chemotherapeutic drug-induced apoptosis.
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Acknowledgements
This work was supported by RGC grants to YC Wong (HKU 7186/99 M, HKU 7314/01 M and HKU 7490/03M) and Area of Excellence Scheme (Project No. AoE/P-10/01).
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Ling, MT., Wang, X., Ouyang, XS. et al. Id-1 expression promotes cell survival through activation of NF-κB signalling pathway in prostate cancer cells. Oncogene 22, 4498–4508 (2003). https://doi.org/10.1038/sj.onc.1206693
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DOI: https://doi.org/10.1038/sj.onc.1206693
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