Abstract 1064: Sloan-Kettering Institute (Ski) protein plays distant roles in activation of Smad proteins in response to nodal and TGF-β in prostate cancer cells

Abstract

Abstract Transforming growth factor-β (TGF-β) acts as a tumor suppressor in the early stages of epithelial cancers by inhibiting proliferation and inducing apoptosis. However, in the later stages of the disease, TGF-β acts as a tumor promoter and is associated with aggressive forms of cancer due to its effects on angiogenesis, immune suppression, and metastasis. Previously, we have demonstrated that Nodal, another member of the TGF-β superfamily and its receptors are expressed in prostate cancer cell lines. Nodal and TGF-β exerted differential effects on prostate cancer cells; both inhibited proliferation in WPE, RWPE1, and DU145 cells while neither had effect on the proliferation of LNCaP and PC3 cells. On the other hand, Nodal and TGF-β induced migration in PC3 cells, but had no effect on cell migration in DU145 cells. Nodal primarily employs Smad2 for intracellular signaling while TGF-β is essential for both Smad2/3 phosphorylations. In the present study, we have determined the expression and role of Ski in Nodal and TGF-β signaling in prostate cancer cells. Ski is a co-repressor of the Smad-mediated TGF-β signaling. Ski was originally classified as an oncogene based on its ability to transform chicken and quail fibroblasts. RT-PCR analysis showed comparable mRNA levels of Ski in several established prostate cell lines; however, high levels of Ski protein were only detected in prostate cancer cell lines and Ski protein levels were very low or absent in normal cells. Ski protein levels were also high in prostate cancer tissue samples compared to normal prostate tissues. Treatment with Nodal and TGF-β had no effects on Ski mRNA levels; however, Nodal had no effect on Ski protein levels while TGF-β induced degradation of Ski protein levels mediated by the proteasome pathway. Reduced Ski levels correlated with increased basal and TGF-β-induced Smad2/3 phosphorylation. Knockdown of endogenous of Ski reduced proliferation in DU145 prostate cancer cells and enhanced migration of PC3 cells. We conclude that high level of Ski expression in prostate cancer cells may be responsible for repression of TGF-β and Smad2/3 signaling, but Ski protein levels do not influence Nodal effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1064. doi:1538-7445.AM2012-1064