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

Previous studies have shown that dexamethasone (Dex) induces the expression of TGF-β1 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-β 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-β receptor type II (TβRII), but not TGF-β receptor type I (TβRI) in a time- and dose-dependent manner. The up-regulation of TβRII expression by Dex was mediated by glucocorticoid receptor and occurred at the transcriptional level. Dex also enhanced TGF-β1 signaling and increased the expression of cyclin-dependent kinase inhibitors p15INK4B (p15) and p27KIP1 (p27), which are the target genes of TGF-β1 and have been identified as inducers of cell cycle arrest at the G1 checkpoint. The antiproliferative effect of Dex was partially blocked by anti-TβRII antibody, indicating that elevated TβRII and TGF-β1 signaling were involved in the antiproliferative effect of Dex. Because the TGF-β1 pathway could not fully explain the antiproliferative effect of Dex, we further examined the effects of Dex on the transcriptional activity of nuclear factor-κB (NF-κB) and the expression of IL-6 and found that Dex suppressed the transcriptional activity of NF-κB 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-β1 signaling, but also through suppressing transcriptional activities of NF-κB.