Induction of steroid sulfatase expression in PC-3 human prostate cancer cells by insulin-like growth factor II.
Human steroid sulfatase (STS) plays an important role in regulating the formation of biologically active estrogens and may be a promising target for treating estrogen-mediated carcinogenesis. The molecular mechanism of STS gene expression, however, is still not clear. Growth factors are known to increase STS activity but the changes in STS expression have not been completely understood. To determine whether insulin-like growth factor (IGF)-II can induce STS gene expression, the effects of IGF-II on STS expression were studied in PC-3 human prostate cancer cells. RT-PCR and Western blot analysis showed that IGF-II treatment significantly increased the expression of STS mRNA and protein in concentration- and time-dependent manners. To understand the signaling pathway by which IGF-II induces STS gene expression, the effects of specific PI3-kinase/Akt and NF-κB inhibitors were determined. When the cells were treated with IGF-II and PI3-kinase/Akt inhibitors, such as LY294002, wortmannin, or Akt inhibitor IV, STS expression induced by IGF-II was significantly blocked. Moreover, we found that NF-κB inhibitors, such as MG-132, bortezomib, Bay 11-7082 or Nemo binding domain (NBD) binding peptide, also strongly prevented IGF-II from inducing STS gene expression. We assessed whether IGF-II activates STS promoter activity using transient transfection with a luciferase reporter. IGF-II significantly stimulated STS reporter activity. Furthermore, IGF-II induced expression of 17β-hydroxysteroid dehydrogenase (HSD) 1 and 3, whereas it reduced estrone sulfotransferase (EST) gene expression, causing enhanced estrone and β-estradiol production. Taken together, these results strongly suggest that IGF-II induces STS expression via a PI3-kinase/Akt-NF-κB signaling pathway in PC-3 cells and may induce estrogen production and estrogen-mediated carcinogenesis.
College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
Chul-Hoon
CH
Sung
Hee-Jung
HJ
Im
Nahee
N
Park
Yeojung
Y
Kwon
Sangyun
S
Shin
Dong-Jin
DJ
Ye
Nam-Hyeon
NH
Cho
Young-Shin
YS
Park
Hyung-Kyoon
HK
Choi
Donghak
D
Kim
Young-Jin
YJ
Chun
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D043266:Steryl-Sulfatase / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077191:Wortmannin
D015067:17-Hydroxysteroid Dehydrogenases; D000730:Androstadienes; D001897:Boronic Acids; D000069286:Bortezomib; D002867:Chromones; D004791:Enzyme Inhibitors; D007335:Insulin-Like Growth Factor II; D007976:Leupeptins; D009025:Morpholines; D016328:NF-kappa B; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D043266:Steryl-Sulfatase; D013450:Sulfones; D015238:Sulfotransferases; D000077191:Wortmannin; C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; C020122:estrone sulfotransferase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
17β-hydroxysteroid dehydrogenase; Akt; EST; HSD; IGF; IL-6; Insulin-like growth factor-II; NBD; NF-κB; PI3-kinase; STS; Steroid sulfatase; TNF; estrone sulfotransferase; insulin-like growth factor; interleukin 6; nemo binding domain; steroid sulfatase; tumor necrosis factor