16alpha-hydroxyestrone inhibits estrogen sulfotransferase activity in human liver cancer cells.
In this study we investigated the impact of estrogen antagonists and of 16alpha-OHE1 (an estrogen derivative that binds to and induces transactivation of estrogen receptors) on estrogen metabolism in malignant HepG2 human liver cells featured by high estrogen sulfotransferase (EST); our aim was to clarify the potential correlation of EST and ER. As expected, the HepG2 cells exhibited a very high EST activity, with the majority of estrogen metabolites (over 86%) being detected as sulfates by 24 h. The coincubation of E2 and the antiestrogen tamoxifen induced a weak inhibition of EST activity (from 85.4% to 81.5%), while the coincubation with the pure antagonist ICI-182 and with 16alpha-OHE1 produced a 50% and 90% decrease of EST, respectively. Interestingly, both selective estrogen receptor modulators (SERMs) TAM and ICI-182, along with the same 16alpha-OHE1, gave rise respectively to a 2.8%, 3.2%, and 4.6% of de novo 16alpha-OHE1 formation. The inhibition of EST and the increase of 16alpha-OHE1 formation were both time- and dose-dependent. Our results suggest that EST activity is tightly associated with ER transactivation and can be regulated by selective estrogen receptor modulators (SERMs), including antiestrogens and 16alpha-OHE1. In this framework, 16alpha-OHE1 may have a potential role in human liver carcinogenesis, also through the inhibition of EST and the production of unconjugated, bioavailable estrogens.
Campisi
Ildegarda
I
Experimental Oncology Units, Department of Oncology, ARNAS-Civico, Palermo, Italy.
Granata
Orazia M
OM
Cocciadiferro
Letizia
L
Calabrò
Maurizio
M
Polito
Lucia M
LM
Carruba
Giuseppe
G
D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006894:Hydroxyestrones / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000201:enzymology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015238:Sulfotransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D006894:Hydroxyestrones; D020845:Selective Estrogen Receptor Modulators; C026702:16-hydroxyestrone; D015238:Sulfotransferases; C020122:estrone sulfotransferase