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Effects of Steroid Hormones and Antisteroids on Alkaline Phosphatase Activity in Human Endometrial Cancer Cells (Ishikawa Line)¹

Department of Obstetrics, Gynecology and Reproductive Science, Mount Sinai School of Medicine, New York, New York 10029 [C. F. H., H. H., E. G.], and Department of Obstetrics and Gynecology, Kitasato University, Kanagawa-Ken, Japan [H. K.]

Alkaline phosphatase activity in human endometrial cancer cells of the estrogen-responsive Ishikawa line was markedly stimulated (3–20-fold in 4 days) by estrogens, 5-dihydrotestosterone, and dehydroepian-drosterone but not by testosterone, medroxyprogesterone acetate, glucocorticoids, several peptide hormones, prostaglandins, or growth factors. Maximum responses to estradiol were obtained at concentrations between 10^-9 and 10^-7 M; at 10^-8 M estradiol, the highest activity was reached 48–72 h after addition of the hormone. A linear relationship between enzyme activity at 48 h and the length of exposure to the hormone was observed. Dibutyryl cyclic guanosine 3':5'-monophosphate, but not dibutyryl cyclic adenosine 3':5'-monophosphate enhanced alkaline phosphatase activity and acted synergistically with estradiol. trans-4-Monohydroxytamoxifen completely antagonized the stimulatory effect of estradiol and had no agonistic activity. Dihydrotestosterone and dehydroepiandrosterone appear to exert their effects, at least in part, by interacting with estrogen receptors, since the simultaneous presence in the medium of monohydroxytamoxifen abolished their influence on alkaline phosphatase activity. The specific antiandrogen monohydroxyflutamide partially antagonized the effect of these hormones, suggesting that their action involved androgenic mechanisms as well.

Exposure to elevated temperature and to specific inhibitors identified alkaline phosphatase of Ishikawa cells as a placental-type isoenzyme, thus contrasting with the nonplacental type found in glandular epithelial cells of normal endometrium and in another human endometrial cancer cell line, HEC-50. This study extends our previous observations of estrogen responsiveness in the Ishikawa cell line. In addition to the previously reported stimulatory effects on growth and progesterone receptor levels, we are now describing the stimulation by estrogens and C₁₉ steroids of an enzyme, alkaline phosphatase, which can be used as a convenient end point to examine mechanisms of hormonal action.

¹ This work was supported by Grant HD 07197, awarded by the National Institute of Child Health and Human Development, and Grant CA 15648, awarded by the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 11/13/85. Revised 2/18/86. Accepted 2/21/86.

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