Membrane androgen receptor activation triggers down-regulation of PI-3K/AKT/NF-kapaB activity and induces apoptotic responses via BAD, FasL and cacpase 3 in DU145 prostate cancer cells.
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-kappaBeta, 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.
Conclusions: 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.
Author: Natalia Papadopoulou, Ioannis Charalampopoulos, Vasileia Anagnostopoulou, Georgios Konstantinidis, Michael Foller, Achilleas Gravanis, Konstantinos Alevizopoulos, Florian Lang and Christos Stournaras
Credits/Source: Molecular Cancer 2008, 7:88
Published on: 2008-12-03
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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