Research

Membrane androgen receptor activation triggers down-regulation of PI-3K/Akt/NF-kappaB activity and induces apoptotic responses via Bad, FasL and caspase-3 in DU145 prostate cancer cells

Natalia Papadopoulou^1* , Ioannis Charalampopoulos^2* , Vasileia Anagnostopoulou¹ , Georgios Konstantinidis¹ , Michael Föller³ , Achilleas Gravanis² , Konstantinos Alevizopoulos⁴ , Florian Lang³ and Christos Stournaras¹

¹  Department of Biochemistry, University of Crete Medical School, Heraklion, Greece

²  Department of Pharmacology, University of Crete Medical School, Heraklion, Greece

³  Department of Physiology, University of Tübingen Medical School, Tübingen, Germany

⁴  Medexis-Biotech SA, Kryoneri, Athens, Greece

author email corresponding author email* Contributed equally

Molecular Cancer 2008, 7:88doi:10.1186/1476-4598-7-88

Published:	3 December 2008

Abstract

Background

Recently we have reported membrane androgen receptors-induced apoptotic regression of prostate cancer cells regulated by Rho/ROCK/actin signaling. In the present study we explored the specificity of these receptors and we analyzed downstream effectors controlling survival and apoptosis in hormone refractory DU145-prostate cancer cells stimulated with membrane androgen receptor-selective agonists.

Results

Using membrane impermeable conjugates of serum albumin covalently linked to testosterone, we show here down-regulation of the activity of pro-survival gene products, namely PI-3K/Akt and NF-κB, in DU145 cells. Testosterone-albumin conjugates further induced FasL expression. A FasL blocking peptide abrogated membrane androgen receptors-dependent apoptosis. In addition, testosterone-albumin conjugates increased caspase-3 and Bad protein activity. The actin cytoskeleton drug cytochalasin B and the ROCK inhibitor Y-27632 inhibited FasL induction and caspase-3 activation, indicating that the newly identified Rho/Rock/actin signaling may regulate the downstream pro-apoptotic effectors in DU145 cells. Finally, other steroids or steroid-albumin conjugates did not interfere with these receptors indicating testosterone specificity.

Conclusion

Collectively, our results provide novel mechanistic insights pointing to specific pro-apoptotic molecules controlling membrane androgen receptors-induced apoptotic regression of prostate cancer cells and corroborate previously published observations on the potential use of membrane androgen receptor-agonists as novel anti-tumor agents in prostate cancer.