Glucocorticoid up-regulates transforming growth factor-beta (TGF-beta) type II receptor and enhances TGF-beta signaling in human prostate cancer PC-3 cells.

Abstract

Previous studies have shown that dexamethasone (Dex) induces the expression of TGF-beta1 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-beta 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-beta receptor type II (TbetaRII), but not TGF-beta receptor type I (TbetaRI) in a time- and dose-dependent manner. The up-regulation of TbetaRII expression by Dex was mediated by glucocorticoid receptor and occurred at the transcriptional level. Dex also enhanced TGF-beta1 signaling and increased the expression of cyclin-dependent kinase inhibitors p15(INK4B) (p15) and p27(KIP1) (p27), which are the target genes of TGF-beta1 and have been identified as inducers of cell cycle arrest at the G1 checkpoint. The antiproliferative effect of Dex was partially blocked by anti-TbetaRII antibody, indicating that elevated TbetaRII and TGF-beta1 signaling were involved in the antiproliferative effect of Dex. Because the TGF-beta1 pathway could not fully explain the antiproliferative effect of Dex, we further examined the effects of Dex on the transcriptional activity of nuclear factor-kappaB (NF-kappaB) and the expression of IL-6 and found that Dex suppressed the transcriptional activity of NF-kappaB 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-beta1 signaling, but also through suppressing transcriptional activities of NF-kappaB.

• Authors: Zongbin Li, Yuxia Chen, Dongmei Cao, Yan Wang, Guangchun Chen, Shimin Zhang, Jian Lu
• Journal: Endocrinology (Endocrinology) Vol. 147 Issue 11 Pg. 5259-67 (Nov 2006) ISSN: 0013-7227 [Print] United States
• PMID: 16887915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p15
• Interleukin-6
• NF-kappa B
• RNA, Messenger
• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Cyclin-Dependent Kinase Inhibitor p27
• Dexamethasone
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p15 (genetics)
• Cyclin-Dependent Kinase Inhibitor p27 (genetics)
• Dexamethasone (pharmacology)
• Gene Expression Regulation (drug effects)
• Humans
• Interleukin-6 (genetics)
• Male
• NF-kappa B (antagonists & inhibitors)
• Promoter Regions, Genetic
• Prostatic Neoplasms
• Protein Serine-Threonine Kinases
• RNA, Messenger (analysis)
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (genetics)
• Signal Transduction (drug effects)
• Transforming Growth Factor beta1 (pharmacology)
• Up-Regulation