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 help support the growth of hormone-dependent cancers, including prostate cancers and is considered as a new promising drug target for treating estrogen-mediated cancer. However, the molecular mechanism of STS expression is still not well-known. Previously, cytokines such as TNF-α and IL-6 were known to increase the activity of STS but the changes in expression have not been completely elucidated. To investigate whether cytokines are able to regulate transcription of STS gene, we studied the effect of TNF-α on STS expression in human prostate cancer PC-3 cells. Western blot and RT-PCR analyses showed that treatment with TNF-α significantly induced expression of mRNA level and protein level of STS in concentration- and time-dependent manners. Treatment with TNF-α resulted in a strong increase in the phosphorylation of Akt on Ser 473 and when the cells were treated with PI3-K inhibitors such as LY294002 or wortmannin or Akt inhibitor (Akt inhibitor IV) together, STS expression induced by TNF-α was significantly blocked. Moreover, inhibition of Akt activation by transfecting dominant-negative Akt plasmid also prevented TNF-α -mediated STS gene expression. Taken together, these data strongly suggest that TNF-α induces STS expression through PI3-K/Akt signaling pathway in PC-3 cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1014. doi:10.1158/1538-7445.AM2011-1014