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

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

^* To whom correspondence should be addressed. E-mail: dxd49{at}case.edu.

	Abstract

Transforming growth factor- (TGF-) functions as a tumor suppressor of the prostate through mechanisms that remain unresolved. Although TGF- receptors directly activate both Smads 2 and 3, to date, Smad3 has been shown to be the essential mediator of most Smad-dependent TGF- 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-–induced apoptosis and gene expression. Parallel analyses revealed that Smad3 is the major mediator of TGF-–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]

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