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Glucocorticoid Up-Regulates Transforming Growth Factor-ß (TGF-ß) Type II Receptor and Enhances TGF-ß Signaling in Human Prostate Cancer PC-3 Cells

Department of Pathophysiology (Z.L., Y.C., D.C., Y.W., G.C., J.L.), the Second Military Medical University, Shanghai 200433, People’s Republic of China; and American Registry of Pathology at Armed Forces Institute of Pathology (S.Z.), Washington, D.C. 20306

Address all correspondence and requests for reprints to: Dr. Jian Lu, Ph.D., Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People’s Republic of China. E-mail: lujian326{at}yahoo.com.

Previous studies have shown that dexamethasone (Dex) induces the expression of TGF-ß1 in androgen-independent prostate cancer both in vitro and in vivo. However, it is not clear whether Dex has a direct effect on the expression of TGF-ß receptors. In this study, using the androgen-independent human prostate cancer cell line, PC-3 cells, we demonstrated that Dex increased the expression of TGF-ß receptor type II (TßRII), but not TGF-ß receptor type I (TßRI) in a time- and dose-dependent manner. The up-regulation of TßRII expression by Dex was mediated by glucocorticoid receptor and occurred at the transcriptional level. Dex also enhanced TGF-ß1 signaling and increased the expression of cyclin-dependent kinase inhibitors p15^INK4B (p15) and p27^KIP1 (p27), which are the target genes of TGF-ß1 and have been identified as inducers of cell cycle arrest at the G1 checkpoint. The antiproliferative effect of Dex was partially blocked by anti-TßRII antibody, indicating that elevated TßRII and TGF-ß1 signaling were involved in the antiproliferative effect of Dex. Because the TGF-ß1 pathway could not fully explain the antiproliferative effect of Dex, we further examined the effects of Dex on the transcriptional activity of nuclear factor-B (NF-B) and the expression of IL-6 and found that Dex suppressed the transcriptional activity of NF-B and IL-6 mRNA expression in PC-3 cells. These results demonstrated that glucocorticoid inhibited the proliferation of PC-3 cells not only through enhancing growth-inhibitory TGF-ß1 signaling, but also through suppressing transcriptional activities of NF-B.