Requirement for NF-(kappa)B in interleukin-4-induced androgen receptor activation in prostate cancer cells.
BACKGROUND
Accumulating evidence suggest a critical role of activation of androgen receptor (AR) by nonandrogen in the development of androgen independent prostate cancer. Previous study identified that interleukin-4 (IL-4) enhances AR activation in the absence of androgen or in the very low levels of androgen in prostate cancer cells. In this study, the mechanism of IL-4-induced AR activation was investigated.


RESULTS
The induction of AR activation by IL-4 can be suppressed by expression of the I(kappa)B(alpha), an inhibitor of NF-(kappa)B. The enhanced expression of AR-mediated prostate-specific antigen (PSA) by IL-4 was blocked by the expression of I(kappa)B(alpha). IL-4 increases NF-(kappa)B transcriptional activity in prostate cancer cells which can be blocked by the addition of IL-4 antibody. IL-4 can also rapidly activate NF-kappaB. Furthermore, the IL-4-induced NF-kappaB activation and nuclear translocation can be blocked by LY294002, a PI3K/Akt specific inhibitor, suggesting that IL-4-induced NF-(kappa)B activation is mediated by activation of PI3K/Akt pathway.


CONCLUSIONS
In combination with previous study that IL-4 activates PI3K/Akt pathway, activation of PI3K/Akt > NF-(kappa)B pathways may be responsible for IL-4-induced AR activation in prostate cancer cells. Taken together, these studies suggest that IL-4 > PI3K/Akt > NF-(kappa)B signaling pathways, which activate AR signaling, may play an important role during the progression of androgen independent prostate cancer cells.
Lee
Soo Ok
SO
Department of Medicine and Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Lou
Wei
W
Nadiminty
Nagalakshmi
N
Lin
Xin
X
Gao
Allen C
AC
D045744:Cell Line, Tumor; D006801:Humans; D015847:Interleukin-4 / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen / Q000502:physiology*; D015398:Signal Transduction
D015847:Interleukin-4; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; C494918:AKT1 protein, human