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 inhibits tumor formation and the symptoms of Cushing syndr...
Retinoic acid inhibits tumor formation and the symptoms of Cushing syndrome. AtT-20 cells were treated with vehicle (a) or 10 nM retinoic acid (b) for 3 hours and then injected into nude mice. (a and b) Representative examples of the mice after 5 weeks (n = 10 in each treatment). Notice the 12-mm-diameter tumor developed by vehicle-treated cells (a). Thinning of the skin was consistently observed in mice with tumors (a). (c–j) Mice with tumors were injected intraperitoneally with 10 mg/kg retinoic acid or vehicle (n = 5 in each experiment) every 4 days for 3 weeks. At the end of the treatment the tumors (c and d) (arrows indicate areas of necrosis), adrenal glands (e–g), and skin samples (h–j) were shock-frozen and analyzed by hematoxylin-eosin staining. Adrenals (e) and skin (h) from vehicle-treated mice without tumors. Tumor (c), adrenals (f), and skin (i) from vehicle-treated mice with tumors. Tumor (d), adrenals (g), and skin (j) from retinoic acid–treated mice with tumors. These results are representative of two independent experiments.