Cyclosporin A potentiates estradiol-induced expression of the cathepsin D gene in MCF7 breast cancer cells.
Although the physiological role of the immunophilins cyclophilin-40 and FKBP52 is unknown, their identification as components of the unactivated estrogen receptor has raised the possibility that they might influence receptor activity in response to the binding of immunosuppressants cyclosporin A and FK506, respectively. We have used Northern analysis to determine the influence of cyclosporin A on the expression of the estrogen-inducible cathepsin D gene in human MCF7 breast cancer cells. We report that 1-3 microM cyclosporin A can potentiate cathepsin D mRNA expression by up to 2-fold in cells treated with 10(-12) to 10(-10) M estradiol. A decreased potentiation effect was noted at higher hormone concentrations. Cyclosporin A alone was unable to induce cathepsin D expression and the increased gene activation observed with combined estradiol/cyclosporin A treatment was negated by the antiestrogen ICI 164,384. Our results suggest that the increased potency of estradiol in the presence of cyclosporin A is associated with an enhanced transcriptional activity of the estrogen receptor and support a role for receptor-associated cyclophilin-40 in the activation process.
Ratajczak
T
T
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia.
Mark
P J
PJ
Martin
R L
RL
Minchin
R F
RF
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D002402:Cathepsin D / Q000235:genetics*; D016572:Cyclosporine / Q000008:administration & dosage*; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011959:Receptors, Estradiol / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D011959:Receptors, Estradiol; D004958:Estradiol; D016572:Cyclosporine; C051781:ICI 164384; D002402:Cathepsin D