Androgens Stimulate the SREBP Pathway in Prostate Cancer Cells by Inducing a Shift in the SCAP-Retention Protein(s) Balance

Abstract

In human prostate cancer (PCA) cells, androgens (As) coordinately stimulate the expression of genes involved in the synthesis of fatty acids and cholesterol. Interestingly, several of these genes are overexpressed in human cancers, particularly those with a poor prognosis, and are promising targets for anti-neoplastic therapy. Exploration of the mechanism underlying the lipogenic effects of As revealed that As induce activation of Sterol Regulatory Element-Binding Proteins (SREBPs), proteolytically activated transcription factors that play a central role in the control of cellular lipid homeostasis. The exact mechanism by which As interfere with the SREBP pathway remains to be investigated. Herein, we show that A-activation of the SREBP pathway depends on the presence of the structural elements required also for its sterol-regulated activation. Detailed studies revealed that As substantially increase the expression of the transporter protein SCAP in 2 of the 3 cell lines tested. Co-transfection of an expression vector encoding SCAP lead to a marked increase in the transcription of a key gene involved in cholesterol synthesis. In support of the involvement of activated SREBPs in the observed effects, SCAP-mediated transcriptional activation of this lipogenic gene was dependent on the presence of intact SREBP binding sites in its promoter region, and was counteracted by addition of dominant-negative SREBP forms. These data suggest that As activate the SREBP pathway by inducing a change in the normal cellular balance between SCAP and its retention protein complex.