Androgen receptor targets NFkappaB and TSP1 to suppress prostate tumor growth in vivo.
The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions. While androgen ablation drives the regression of normal and cancerous prostate, testosterone may cause both proliferation and apoptosis. Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor (AR), however no mechanistic explanation was offered. In this paper we demonstrate in vivo anti-tumor effect of the AR on prostate cancer growth and identify its molecular mediators. We analyzed the effect of AR on the tumorigenicity of prostate cancer cells. Unexpectedly, the AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls. Moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis. AR expression lowered the angiogenic potential of cancer cells, by increasing secretion of an anti-angiogenic protein, thrombospondin-1. AR activation caused a decrease in RelA, a subunit of the pro-survival transcription factor NFkappaB, reduced its nuclear localization and transcriptional activity. This, in turn, diminished the expression of its anti-apoptotic targets, Bcl-2 and IL-6. Increased apoptosis within AR-expressing tumors was likely due to the NFkappaB suppression, since it was restricted to the cells lacking nuclear (active) NFkappaB. Thus we for the first time identified combined decrease of NFkappaB and increased TSP1 as molecular events underlying the AR anti-tumor activity in vivo. Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal, a standard treatment for early-stage prostate cancer. (c) 2007 Wiley-Liss, Inc.
Nelius
Thomas
T
Department of Urology, Texas Tech University Health Sciences Center, Texas Tech University, Lubbock, TX.
Filleur
Stephanie
S
Yemelyanov
Alexander
A
Budunova
Irina
I
Shroff
E
E
Mirochnik
Yelena
Y
Aurora
Arin
A
Veliceasa
Dorina
D
Xiao
Wuhan
W
Wang
Zhou
Z
Volpert
Olga V
OV
D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017077:Culture Media, Conditioned; D017931:DNA Primers; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017077:Culture Media, Conditioned; D017931:DNA Primers; D015850:Interleukin-6; D016328:NF-kappa B; D011944:Receptors, Androgen; C481348:SPZ1 protein, human