%0 Journal Article
%T Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells
%A Mengqian Chen
%A Michael A Feuerstein
%A Elina Levina
%A Prateek S Baghel
%A Richard D Carkner
%A Matthew J Tanner
%A Michael Shtutman
%A Francis Vacherot
%A St¨¦phane Terry
%A Alexandre de la Taille
%A Ralph Buttyan
%J Molecular Cancer
%D 2010
%I BioMed Central
%R 10.1186/1476-4598-9-89
%X Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.Collectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.When detected in the advanced stage, prostate cancer patients are treated with hormone therapies that reduce systemic androgen levels [1-3]. This action palliates the symptoms of metastases, induces regression of metastatic lesions and slows prostate tumor growth [4]. Over time, however, the cancer can recur in a castration resistant form (CRPC) that continues to
%U http://www.molecular-cancer.com/content/9/1/89