RelB enhances prostate cancer growth: implications for the role of the nuclear factor-kappaB alternative pathway in tumorigenicity.
The nuclear factor-kappaB (NF-kappaB) classic pathway is thought to be critical for tumorigenesis, but little is known about the role of the NF-kappaB 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 RelB contributes to tumorigenicity of prostate cancer. Inhibiting RelB 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-kappaB 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 RelB 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-kappaB alternative pathway as a potential target for preventing prostate cancer, and suggest the use of IL-8 as a marker for prostate cancer prognosis.
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536, USA.
Yong
Y
Xu
Sajni
S
Josson
Fang
F
Fang
Terry D
TD
Oberley
Daret K
DK
St Clair
X Steven
XS
Wan
Yulan
Y
Sun
Vasudevan
V
Bakthavatchalu
Anantharaman
A
Muthuswamy
William H
WH
St Clair
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D016328:NF-kappa B; C497593:RELB protein, human; D034741:RNA, Small Interfering; D051841:Transcription Factor RelB