17β-Hydroxysteroid dehydrogenase activity in endometrial cancer cells: Different metabolic pathways of estradiol in hormone-responsive and non-responsive intact cells

In this paper we report that two human long-term endometrial cancer cell lines, Ishikawa and HEC-1A, exhibit quite different abilities in metabolizing estrogens. As a matter of fact, incubation of Ishikawa cells with close-to-physiological concentrations of estradiol (E₂) as precursor resulted in: (1) elevated formation (up to 90%) of E₂-sulphate (E₂-S), using lower precursor concentrations; (2) very limited conversion to estrone (E₁) (< 10% at 24 h incubation), as either free or sulphate; and (3) low but consistent production of other estrogen derivatives, such as 2-hydroxy-estrogens and estriol. Conversely, scant amounts (if any) of E₂-S were found in HEC-1A cells, while no detectable formation of other estrogen metabolites could be observed after 24 h. On the other hand, E₁ production was significantly greater (nearly 60% at 24 h) than in Ishikawa cells, a large proportion of E₁ (over 50% of the total) being formed after only 6 h incubation using time-course experiments. The hypothesis that E₂ metabolism could be minor in Ishikawa cells as a consequence of the high rate of E₂-S formation encountered is contradicted by the evidence that conversion to E₁ also remains limited in the presence of much lower E₂-S amounts, seen using higher molar concentrations of precursor. Overall, we observe that 17β-hydroxysteroid dehydrogenase (17β-HSD) activity diverges significantly in intact Ishikawa and HEC-1A endometrial cancer cells. This difference could not merely be accounted for by the diverse amounts of substrate (E₂) available to the cells, nor may it be imputed to different levels of endogenous estrogens. It should rather be sought in different mechanisms controlling 17β-HSD activity or, alternatively, in the presence of distinct isoenzymes in the two different cell types.