Exp Mol Med.  2011 Nov;43(11):646-652. 10.3858/emm.2011.43.11.073.

Induction of steroid sulfatase expression by tumor necrosis factor-alpha through phosphatidylinositol 3-kinase/Akt signaling pathway in PC-3 human prostate cancer cells

• Suh BY
• Jung JJ
• Park N
• Seong CH
• Im HJ
• Kwon Y
• Kim D
• Chun YJ

• KMID: 1025168
• DOI: http://doi.org/10.3858/emm.2011.43.11.073

Abstract

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.

Keyword

phosphatidylinositol 3-kinase; prostate neoplasms; proto-oncogene proteins c-akt; steryl-sulfatase; tumor necrosis factor-alpha

MeSH Terms

Blotting, Western
Fluorescent Antibody Technique
Humans
Male
Phosphatidylinositol 3-Kinase/genetics/*metabolism
Phosphorylation/drug effects
Prostatic Neoplasms/genetics/*metabolism
Proto-Oncogene Proteins c-akt/genetics/*metabolism
RNA, Messenger/genetics
Real-Time Polymerase Chain Reaction
Recombinant Proteins/genetics/isolation & purification/metabolism
Signal Transduction
Steryl-Sulfatase/genetics/*metabolism
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha/*pharmacology