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 ; 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

BACKGROUND: Epidural anesthesia has been shown to a have direct sedative effect and to markedly reduce the amount of hypnotic agents required for sedation. A Bispectral Index (BIS) is a useful monitor of the level of sedation and loss of consciousness for several anesthetics including propofol. In this study, we investigated whether BIS monitoring could detect the sedative effect of epidural anesthesia during propofol induction. METHODS: Twenty patients scheduled for elective lower abdominal surgery were included. A Target controlled infusion (target effect concentration 5micro gram/ml, induction time 3 min) of propofol was administered to the patients with or without epidural anesthesia (2% lidocaine 15 ml) at the L2-3 level. The OAA/S scale and BIS were evaluated 20 min after epidural injection. Hypnotic requirements of propofol were determined using loss of eye opening in response to verbal command as an endpoint. At the time of induction of hypnosis, the target concentration, target effect concentration and BIS were recorded. RESULTS: Epidural lidocaine significantly decreased the hypnotic dose of propofol (1.0 +/- 0.2 micro gram/ml vs. 1.3 +/- 0.1 micro gram/ml; P = 0.0008), hypnotic calculated concentration (3.3 +/- 0.6 micro gram/ml vs. 4.1 +/- 0.3 micro gram/ml; P = 0.0007), and the hypnotic effect concentration (0.7 +/- 0.3micro gram/ml vs. 1.1 +/- 0.1 micro gram/ml; P = 0.0007). In the patients with epidural anesthesia, the OAA/S scale was decreased without a change of the BIS after epidural anesthesia and BIS recorded at the time of induction of hypnosis was much higher in patients with epidural anesthesia than in patients without epidural anesthesia (92.7 +/- 2.2 vs. 85.5 +/- 6.2; P = 0.0029) CONCLUSIONS: Epidural anesthesia induced a sedative effect without a change of the BIS and then induced the hypnosis with lesser dose of propofol. At the time of hypnosis, a higher BIS was noticed with epidural anestheia. These results concluded that BIS monitoring could not detect the sedative effect induced with epidural anesthesia.
Anesthesia, Epidural* ; Anesthetics ; Consciousness Monitors* ; Humans ; Hypnosis ; Hypnotics and Sedatives* ; Injections, Epidural ; Lidocaine ; Propofol ; Unconsciousness