RU486, a progestin antagonist, binds to progesterone receptors in a human endometrial cancer cell line and reverses the growth inhibition by progestins.
The human endometrial cancer cell line, IK-90 cells, contains estrogen-independent progesterone receptors (PR) and is progestin sensitive. Accumulation of glycogen in the cytoplasm of IK-90 cells as well as growth inhibition of the cells in response to progestins are observed. In the present study, the effects of RU486, a progestin antagonist, on IK-90 cells were investigated in a serum-supplemented medium. Scatchard plot analysis of cytoplasmic binding data in the cells revealed a high affinity binding site for RU486 (Kd, 2.6 nM) with maximum binding sites of 169 fmol/mg protein. However, the binding ability to DNA-cellulose of heat activated [3H]RU486-PR complexes was lower when compared with that of the progestin agonist [3H]R5020-PR complexes, suggesting a decrease in progestin activity of RU486 in IK-90 cells. The addition of 1 microM RU486 to culture medium produced periodic acid-Schiff-positive granules in the cytoplasm of the cells. On the other hand, RU486 (1 nM-1 microM) did not significantly inhibit the growth of cells. However, RU486 (0.1-1 microM) totally prevented the growth-inhibitory effect of R5020 (0.1-1 microM) on IK-90 cells. In conclusion, RU486, an antiprogestin, had a dual activity both a progestin antagonist and weak agonist in human endometrial cancer cells, which was not mediated through the estrogen receptor system.
Terakawa
N
N
Department of Obstetrics and Gynecology, Osaka University Medical School, Japan.
Shimizu
I
I
Tanizawa
O
O
Matsumoto
K
K
D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002482:Cellulose / Q000031:analogs & derivatives / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000031:analogs & derivatives / Q000378:metabolism; D004963:Estrenes / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D015735:Mifepristone; D010503:Periodic Acid-Schiff Reaction; D011372:Progestins / Q000037:antagonists & inhibitors*; D011397:Promegestone / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D013194:Staining and Labeling; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000378:metabolism*
C033190:DNA-cellulose; D004963:Estrenes; D011372:Progestins; D011980:Receptors, Progesterone; D015735:Mifepristone; D002482:Cellulose; D006003:Glycogen; D004247:DNA; D011397:Promegestone