RelB Enhances Prostate Cancer Growth: Implications for the Role of the Nuclear Factor-κB Alternative Pathway in Tumorigenicity

The nuclear factor-kappa B (NF-kappa B) classic pathway is thought to be critical for tumorigenesis, but little is known about the role of the NF-kappa B alternative pathway in cancer development. Recently, high constitutive nuclear levels of RelB have been observed in human prostate cancer specimens with high Gleason scores. Here, we used four complementary approaches to test whether ROB contributes to tumorigenicity of prostate cancer. Inhibiting ROB in aggressive androgen-independent PC-3 cells by stable or conditional expression of a dominant-negative p100 mutant significantly reduced the incidence and growth rate of tumors. The decrease in tumorigenicity coincided with a reduction in the NF-kappa B target interleukin-8 (IL-8). Consistently, down-regulation of RelB by small interfering RNA targeting also reduced tumor growth and decreased levels of IL-8. Conversely, stable expression of ROB in androgen-responsive LNCaP tumors increased the circulating IL-8 levels. Taken together, these results reveal a tumor-supportive role of RelB, implicate the NF-kappa B alternative pathway as a potential target for preventing prostate cancer, and suggest the use of IL-8 as a marker for prostate cancer prognosis, [Cancer Res 2009;69(8):3267-71]