Paracrine Hedgehog Stimulates Androgen Production From Prostate Stromal Fibroblasts

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011269 PARACRINE HEDGEHOG STIMULATES ANDROGEN PRODUCTION FROM PROSTATE STROMAL FIBROBLASTS Elina Levina, Richard Carkner, Michael Shtutman, Mengqian Chen, and Ralph Buttyan Elina LevinaElina Levina Albany, NY More articles by this author , Richard CarknerRichard Carkner Albany, NY More articles by this author , Michael ShtutmanMichael Shtutman Albany, NY More articles by this author , Mengqian ChenMengqian Chen Albany, NY More articles by this author , and Ralph ButtyanRalph Buttyan Albany, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.361AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hedgehog (Hh) is a paracrine signaling pathway that regulates Gli-mediated transcription, tissue morphogenesis and cell fate determination during development. Paracrine Hh also promotes androgen biosynthesis from testis/ovaries. When androgen deprived, human prostate cancer (PrCa) cells secrete Hh ligands and this is thought to play a role in PrCa progression to castration resistant disease (CRPC) through paracrine effects on non-malignant cells surrounding a prostate tumor. Here, we sought to characterize the effects of Hh stimulation on human prostate stromal cells (PrSCs) to better understand the role of Hh in PrCa progression. METHODS Primary human PrSCs (from 2 different donors) were treated with a Hh agonist, SAG, and the effects on gene expression were characterized by comparative gene expression profiling using Affymetrix human ST1.0 gene Chips. Differences in gene expression between SAG-treated or -untreated cells were confirmed by quantitative real-time RT-PCR. Transduction of PrSCs with Gli2 lentivirus or treatment of SAG-stimulated PrSCs with Gli2 siRNAs were used to test for a role of Gli transcription in SAG-induced changes. PrSCs were grown in the presence of 10μM dehydroepiandrosterone (DHEA) with or without SAG stimulation and conditioned medium was tested for testosterone (T) or dihydrotestosterone (DHT) using ELISA-based assays. PrSCs were transduced with SREBPF-1 and 17βHSD7 lentivirus to test whether these genes increase conversion of DHEA to T in PrSCs. RESULTS Of 41 genes significantly upregulated in PrSCs by SAG treatment, 30 are functionally involved in cholesterol/steroid hormone biosynthesis including SREBPF-1 and 17βHSDB7. Transduction with active Gli2 induces many of these genes and Gli2 siRNAs block their induction after SAG-stimulation, confirming the SAG effect depends on Gli transcription. SAG-stimulated PrSCs produce twice as much T and DHT from DHEA as unstimulated cells. Transduction with SREBPF-1 or 17βHSD7 also significantly increases T output from DHEA in PrSCs. CONCLUSIONS Activation of Hh signaling in benign human PrSCs specifically upregulated genes involved in cholesterol/steroid hormone biosynthesis. Additionally, we show that Hh signaling significantly increases conversion of DHEA to T/DHT in these cells and this action could mediate increased androgen biosynthesis from androgen-deprived prostate tumors that supports CRPC growth. Finally, our work suggests that SREBPF-1 is a primary target of Hh/Gli action in PrSCs and that this protein induces downstream genes involved in metabolism of DHEA to androgens. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e108 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Elina Levina Albany, NY More articles by this author Richard Carkner Albany, NY More articles by this author Michael Shtutman Albany, NY More articles by this author Mengqian Chen Albany, NY More articles by this author Ralph Buttyan Albany, NY More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...