Glucocorticoid up-regulates transforming growth factor-beta (TGF-beta) type II receptor and enhances TGF-beta signaling in human prostate cancer PC-3 cells.
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.
Li
Zongbin
Z
Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People's Republic of China.
Chen
Yuxia
Y
Cao
Dongmei
D
Wang
Yan
Y
Chen
Guangchun
G
Zhang
Shimin
S
Lu
Jian
J
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000032:analysis; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D015854:Up-Regulation
D050762:Cyclin-Dependent Kinase Inhibitor p15; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II