| The constitutive activity of the redox sensitive transcription factor NF-kappaB is high in advanced androgen independent prostate cancer cells. With the exception of RelB, the role of NF-kappaB family members in cancer has been extensively investigated. This study, for the first time demonstrates a crucial role of RelB in enhancing oxidative stress response and tumorigenesis in androgen independent prostate cancers. To elucidate the radio-protective mechanism of RelB, two approaches were used to inhibit RelB function, i.e. ectopically expres sed dominant negative inhibitor, p100 mutant and RelB siRNA. Blocking RelB by both approaches resulted in significant decrease in radiation resistance of prostate cancer cells. In response to radiation, an increased RelB DNA binding to the promoter of the NF-kappaB target gene, Manganese superoxide dismutase (MnSOD) was detected. This response results in a time dependent increase in MnSOD mRNA and protein, suggesting a transcription mediated mechanism of the observed effect. Consistent with the transcriptional role of RelB, the constitutive levels of MnSOD protein decreased and MnSOD was not induced in response to radiation in the RelB inhibited cells. These results suggest that the activation of RelB leading to the induction of MnSOD plays an important role in the radio-protective mechanism of RelB in prostate cancer cells.; RelB is shown to be overexpressed in prostate cancer tissue with high Gleason score and poor outcome. Nuclear RelB levels are shown to increase in prostate cancer cells with higher tumorigenicity. Selective inhibition of RelB using the p100 dominant negative significantly reduced the incidence of tumor development and the tumor growth rate suggesting an important role of ROB in prostate tumorigenesis. Consistent with these findings, inhibition of RelB using siRNA resulted in decreased cell viability of PC-3 cells. Inhibition of RelB also led to a decrease in Bcl-xL and survivin mRNA and protein. This suggests that RelB transcriptionally regulates oncogenes and plays an important role in cancer cell survival. Therefore, selective inhibition of RelB preferentially inhibits the transcription of antioxidant and pro-survival genes, suppresses tumorigenicity and increases intrinsic radiation sensitivity of prostate cancer cells. Therefore, as RelB levels are high in prostate cancers compared to normal prostate tissue, RelB could be selectively targeted for cancer treatment. These results reveal a novel role for RelB in the control of aggressive prostate cancer, with critical consequences for their intrinsic radiation resistance. |
