The nuclear factor-kappaB pathway controls the progression of prostate cancer to androgen-independent growth.
Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an "androgen-independent" stage that results in renewed growth and spread of the cancer. Both nuclear factor-kappaB (NF-kappaB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-kappaB pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-kappaB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-kappaB signaling in vivo by the absence of the IkappaBalpha inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-kappaB pathway was activated in the ARR(2)PB-myc-PAI (Hi-myc) mouse prostate by cross-breeding into a IkappaBalpha(+/-) haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-kappaB is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating AR action. Thus, the NF-kappaB pathway may be a potential target for therapy against androgen-independent prostate cancer.
Jin
Ren Jie
RJ
Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, A1329 MCN, 1161 21st Avenue South, Nashville, TN 37232-2765, USA.
Lho
Yongsoo
Y
Connelly
Linda
L
Wang
Yongqing
Y
Yu
Xiuping
X
Saint Jean
Leshana
L
Case
Thomas C
TC
Ellwood-Yen
Katharine
K
Sawyers
Charles L
CL
Bhowmick
Neil A
NA
Blackwell
Timothy S
TS
Yull
Fiona E
FE
Matusik
Robert J
RJ
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018278:Carcinoma, Neuroendocrine / Q000473:pathology*; D002369:Castration; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C410798:AR protein, human; D000728:Androgens; D016328:NF-kappa B; D012333:RNA, Messenger; D011944:Receptors, Androgen; D051550:I-kappa B Kinase