Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

Abstract

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 NFjB, 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 NFjB suppression, since it was restricted to the cells lacking nuclear (active) NFjB. Thus we for the first time identified combined decrease of NFjB 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. ' 2007 Wiley-Liss, Inc.

BRCA1, BRCA2, AR and IGF-I expression in prostate cancer: Correlation between RT-qPCR and immunohistochemical detection

“…other researchers demonstrated in vivo the antitumor effect of the AR on prostate cancer growth. AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls and, moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis (45). By immunohistochemistry, we found a greater frequency of nuclear overexpression of AR in normal prostate tissues than in the adenocarcinomas.…”

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…Moreover, when PC-3-v or PC-3-AR9 cells were co-cultured with WMPY1 stromal cells (Webber et al, 1999) and orthotopically transplanted in nude mice, PC-3-AR9 co-cultured cells still produced smaller primary and metastatic tumors than PC-3-v co-cultured cells, suggesting that even in the presence of stromal AR stimulation, the suppressor function of the epithelial AR remains effective. Using transfectants of PC-3 cells with an inducible AR-expressing transgene, Nelius et al (2007) also observed that induction of AR expression in an inducible PC-3-AR þ line resulted in an androgendependent decrease in invasion in vitro and decreased tumorigenecity because of decreased microvascular density that led to increased tumor cell apoptosis after subcutaneous inoculation in nude mice.…”

Novel Steroid Receptor Phyto-Modulator Compound A Inhibits Growth and Survival of Prostate Cancer Cells

“…The interaction between AR and other TFs is much less studied. However, there is growing evidence that AR interacts with other TFs, including AP-1, NF-nB, and Ets family members, and this interaction can modulate activity of those TFs and consequently the transcription of their target genes (3,10,17,18).…”