1195 PSA-INDUCED OSTEOBLASTIC DIFFERENTIATION IN SAOS-2 CELLS: ROLE OF WIF-1 AND TGF-BETA

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research VI1 Apr 20101195 PSA-INDUCED OSTEOBLASTIC DIFFERENTIATION IN SAOS-2 CELLS: ROLE OF WIF-1 AND TGF-BETA Nagalakshmi Nadiminty, Wei Lou, and Allen Gao Nagalakshmi NadimintyNagalakshmi Nadiminty More articles by this author , Wei LouWei Lou More articles by this author , and Allen GaoAllen Gao More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.696AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The high prevalence of osteoblastic bone metastases in prostate cancer likely involves the production of osteoblast-stimulating factors by prostate cancer cells. The identity of the factors responsible for the homing of circulating prostate cancer cells to the bone remains unknown. Prostate specific antigen (PSA) is a serine protease produced by prostate cancer cells and is an important serological marker for prostate cancer. In this study, we examined the involvement of Wnt inhibitory factor 1 (Wif-1) and Transforming growth factor beta (TGF-beta) in osteoblastic differentiation induced by PSA in SaOS-2 human osteosarcoma cells. METHODS Microarray analysis of RNAs from Saos-2 cells stably expressing PSA and vector controls was performed and the results were validated by northern blotting. The potential role of Wif-1 and TGF-β in osteoblatic differentiation induced by PSA was examined by alkaline phosphatase assays, luciferase assays and northern analysis. RESULTS PSA was found to induce bone remodeling in SaOS-2 cells as evidenced by increases in alkaline phosphatase activity, mineral deposition and osteogenic gene expression. Saos-2 cells expressing PSA exhibited markedly upregulated expression of markers of osteoblastic differentiation like collagen type 1, osteocalcin, Runx-2, alkaline phosphatase and bone sialoprotein compared to parental Saos-2 cells and vector controls. Treatment of SaOS cells with exogenous enzymatically active PSA produced similar results, suggesting that osteoblastic differentiation may be regulated by PSA. Among the genes found to be regulated by PSA expression, TGF-beta and Wif-1 were examined further. PSA enhanced the expression and activation of TGF-beta as shown by higher levels of TGF-beta-responsive reporter activity and increase in expression of TGF-beta receptors I and II. Overexpression of Wif-1 in SaOS-2 cells enhanced osteogenic gene expression, while inhibition of Wif-1 expression in PSA-expressing cells resulted in reduction of alkaline phosphatase activity, a marker of osteoblastic differentiation. CONCLUSIONS PSA-induced bone remodeling was mediated by enhanced expression of several markers of osteoblastic differentiation and modulation of TGF-beta and the Wnt/beta-catenin pathways. These results suggest that PSA produced by metastatic prostate cancer cells may participate in bone remodeling in favor of development of osteoblastic metastases. These findings provide a molecular basis for understanding the high prevalence of osteoblastic bone metastases in prostate cancer. Sacramento, CA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e463 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nagalakshmi Nadiminty More articles by this author Wei Lou More articles by this author Allen Gao More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...