Retinoic acid prevents experimental Cushing syndrome

M Páez-Pereda

D Kovalovsky

U Hopfner

M Theodoropoulou

Y Grübler+3 authors

^{Max Planck Institute of Psychiatry, Munich, Germany}^{Laboratorio de Fisiología y Biología Molecular, Universidad de Buenos Aires and Argentine National Research Council (CONICET), Ciudad Universitaria, Buenos Aires, Argentina}^{Department of Neurosurgery, University of Munich, Munich, Germany}^{Department of Neurosurgery, San Raffaele Scientific Research Institute (IRCCS) San Raffaele, University of Milano, Milano, Italy}^{Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy}

Address correspondence to: Marcelo Páez-Pereda, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany. Phone: 49-89-30622-272; Fax: 49-89-30622-605; E-mail: ed.gpm.lkyspipm@olecram.

Received 2000 Aug 17; Accepted 2001 Aug 27.

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.

Abstract

Acknowledgments

We thank M. Low (Vollum Institute, Portland, Oregon, USA) for the POMC-LUC construct, J. Drouin (University of Montréal, Quebec, Canada) for the NurRE and NBRE reporters and the POMC promoter with a mutated NurRE site, and M. Tsai (Baylor College of Medicine, Houston, Texas, USA) for the COUP-TFI expression vector. We also thank W. Bollag (Roche, Basel, Switzerland) and O. Almeida (Max Planck Institute of Psychiatry, Munich, Germany) for comments on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (Sta 285/7-3) and the Volkswagen Foundation (I/76 803).

Acknowledgments

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