title: Retinoic acid prevents experimental Cushing syndrome.
abstract: Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany. marcelo@mpipsykl.mpg.de
authors.forename: M
authors.initials: M
authors.lastname: Páez-Pereda
authors.forename: D
authors.initials: D
authors.lastname: Kovalovsky
authors.forename: U
authors.initials: U
authors.lastname: Hopfner
authors.forename: M
authors.initials: M
authors.lastname: Theodoropoulou
authors.forename: U
authors.initials: U
authors.lastname: Pagotto
authors.forename: E
authors.initials: E
authors.lastname: Uhl
authors.forename: M
authors.initials: M
authors.lastname: Losa
authors.forename: J
authors.initials: J
authors.lastname: Stalla
authors.forename: Y
authors.initials: Y
authors.lastname: Grübler
authors.forename: C
authors.initials: C
authors.lastname: Missale
authors.forename: E
authors.initials: E
authors.lastname: Arzt
authors.forename: G K
authors.initials: GK
authors.lastname: Stalla
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis; D000818:Animals; D051838:COUP Transcription Factor I; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D003480:Cushing Syndrome / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018358:Neuroendocrine Tumors / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D051838:COUP Transcription Factor I; D004268:DNA-Binding Proteins; C497589:NR2F1 protein, human; C497590:Nr2f1 protein, mouse; D014157:Transcription Factors; D014212:Tretinoin; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone