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Critical Role of Smad2 in Tumor Suppression and Transforming Growth Factor-β–Induced Apoptosis of Prostate Epithelial Cells

¹ The Case Comprehensive Cancer Center, Departments of ² Pharmacology and ³ Biochemistry, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio

Requests for reprints: David Danielpour, WRB 3532, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106. Phone: 216-368-5670; Fax: 216-368-8919; E-mail: dxd49{at}case.edu.

Key Words: prostate cancer • Smad • lentivirus • shRNA • nude mice

Transforming growth factor-β (TGF-β) functions as a tumor suppressor of the prostate through mechanisms that remain unresolved. Although TGF-β receptors directly activate both Smads 2 and 3, to date, Smad3 has been shown to be the essential mediator of most Smad-dependent TGF-β responses, including control of gene expression, cell growth, apoptosis, and tumor suppression. Using a robust lentiviral short hairpin RNA system to silence Smads 2 and/or 3 in the NRP-152 nontumorigenic rat prostate basal epithelial cell line, we provide the first evidence for Smad2 as a critical mediator of TGF-β–induced apoptosis and gene expression. Parallel analyses revealed that Smad3 is the major mediator of TGF-β–induced transcriptional and apoptotic responses in the NRP-154 rat prostate carcinoma cell line. Remarkably, silencing Smad2 alone caused malignant transformation of NRP-152 cells, as assayed by s.c. tumor growth in athymic mice, whereas silencing Smad3 alone did not induce tumors. Nevertheless, tumors induced by silencing both Smads 2 and 3 were larger than those from silencing Smad2 alone. Given previous reports that NRP-152 cells have a stem cell phenotype, we speculate a critical role for Smad2 as a tumor suppressor in the basal epithelial or stem cell compartment of the prostate. [Cancer Res 2009;69(6):2185–90]