1.Induction of steroid sulfatase expression by tumor necrosis factor-alpha through phosphatidylinositol 3-kinase/Akt signaling pathway in PC-3 human prostate cancer cells.
Bo Young SUH ; Jin Joo JUNG ; Nahee PARK ; Cheul Hun SEONG ; Hee Jung IM ; Yeojung KWON ; Donghak KIM ; Young Jin CHUN
Experimental & Molecular Medicine 2011;43(11):646-652
Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and has a pivotal role in regulating the formation of biologically active estrogens. STS may be considered a new promising drug target for treating estrogen-mediated carcinogenesis. However, the molecular mechanism of STS expression is not well-known. To investigate whether tumor necrosis factor (TNF)-alpha is able to regulate gene transcription of STS, we studied the effect of TNF-alpha on STS expression in PC-3 human prostate cancer cells. RT-PCR and Western blot analysis showed that TNF-alpha significantly induced the expression of STS mRNA and protein in a concentration- and time-dependent manner. Treatment with TNF-alpha resulted in a strong increase in the phosphorylation of Akt on Ser-473 and when cells were treated with phosphatidylinositol (PI) 3-kinase inhibitors such as LY294002 or wortmannin, or Akt inhibitor (Akt inhibitor IV), induction of STS mRNA expression by TNF-alpha was significantly prevented. Moreover, activation of Akt1 by expressing the constitutively active form of Akt1 increased STS expression whereas dominant-negative Akt suppressed TNF-alpha-mediated STS induction. We also found that TNF-alpha is able to increase STS mRNA expression in other human cancer cells such as LNCaP, MDA-MB-231, and MCF-7 as well as PC-3 cells. Taken together, our results strongly suggest that PI 3-kinase/Akt activation mediates induction of human STS gene expression by TNF-alpha in human cancer cells.
Blotting, Western
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Fluorescent Antibody Technique
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Humans
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Male
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Phosphatidylinositol 3-Kinase/genetics/*metabolism
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Phosphorylation/drug effects
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Prostatic Neoplasms/genetics/*metabolism
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Proto-Oncogene Proteins c-akt/genetics/*metabolism
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RNA, Messenger/genetics
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Real-Time Polymerase Chain Reaction
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Recombinant Proteins/genetics/isolation & purification/metabolism
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Signal Transduction
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Steryl-Sulfatase/genetics/*metabolism
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha/*pharmacology