Retinoic acid prevents experimental Cushing syndrome
Marcelo Páez-Pereda, … , Eduardo Arzt, Günter K. Stalla
Marcelo Páez-Pereda, … , Eduardo Arzt, Günter K. Stalla
Published October 15, 2001
Citation Information: J Clin Invest. 2001;108(8):1123-1131. https://doi.org/10.1172/JCI11098.
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Article

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

Marcelo Páez-Pereda, Damian Kovalovsky, Ursula Hopfner, Marily Theodoropoulou, Uberto Pagotto, Eberhard Uhl, Marco Losa, Johanna Stalla, Yvonne Grübler, Cristina Missale, Eduardo Arzt, Günter K. Stalla

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Retinoic acid specifically inhibits ACTH production in human neuroendocr...
Retinoic acid specifically inhibits ACTH production in human neuroendocrine tumors. (a) Human pituitary adenoma cells from eight patients with Cushing disease were treated with 10 nM or 100 nM retinoic acid (RA) for 24 hours, and ACTH was measured by RIA in the supernatants. Values at the top represent the basal ACTH production of each tumor, and the bars indicate percentages of these values after retinoic acid treatment. (b) NCI-N-592 small-cell lung cancer cells were treated with retinoic acid. After 24 hours, ACTH was measured in the supernatants. (c–e) Normal rat pituitary cells were treated for 24 hours with retinoic acid (RA), 5 μM forskolin (Forsk), 10 nM hydrocortisone (HC), 100 nM thyrotropin-releasing hormone (TRH), 1 μM bromocriptine (BrCr), 100 nM growth hormone–releasing hormone (GHRH), or 100 nM octreotide (Oct). Supernatants were collected and ACTH (c), prolactin (d), and growth hormone (GH) (e) were measured by RIA. Averages of four wells per treatment and the corresponding SEs are shown. *P < 0.001 compared with the corresponding basal values, **P < 0.01 compared with the stimulated values, determined by ANOVA in combination with the Scheffé test. b–e are representative of three independent experiments. (f) COUP-TFI expression was detected in normal human pituitary (n = 3) by immunoperoxidase staining (diaminobenzidine brown color). Inset: negative control. (g) Double immunohistochemistry for COUP-TFI (brown color, filled arrows) and ACTH (vector red color, open arrows). (h) COUP-TFI immunohistochemistry in Cushing adenomas was negative (n = 7).