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

Thomas Nelius, Stephanie Filleur, Alexander Yemelyanov, Irina Budunova, E. Shroff, Yelena Mirochnik, Arin Aurora, Dorina Veliceasa, Wuhan Xiao, Zhou Wang, Olga V. Volpert*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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 NFκB, 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 NFκB suppression, since it was restricted to the cells lacking nuclear (active) NFκB. Thus we for the first time identified combined decrease of NFκB 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.

Original languageEnglish (US)
Pages (from-to)999-1008
Number of pages10
JournalInternational Journal of Cancer
Volume121
Issue number5
DOIs
StatePublished - Sep 1 2007

Keywords

  • Androgen receptor
  • Angiogenesis
  • Apoptosis
  • NFκB
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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