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Retinoic acid prevents experimental Cushing syndrome
M Páez-Pereda1, D Kovalovsky, U Hopfner
1Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany. marcelo@mpipsykl.mpg.de
The Journal of Clinical Investigation
|October 17, 2001
Summary
Retinoic acid effectively reduces adrenocorticotropic hormone (ACTH) and corticosterone production in experimental Cushing syndrome. This treatment also inhibits tumor cell proliferation and induces cell death, reversing key endocrine alterations.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Cushing syndrome results from excess adrenocorticotropic hormone (ACTH) production, often by neuroendocrine tumors, leading to chronic glucocorticoid excess.
- Neuroendocrine tumors secreting ACTH are the primary cause of Cushing syndrome, characterized by elevated glucocorticoid levels.
Purpose of the Study:
- To investigate the effects of retinoic acid on ACTH-secreting tumor cells and its potential therapeutic role in Cushing syndrome.
- To determine retinoic acid's impact on pro-opiomelanocortin transcription, ACTH production, and tumor cell proliferation.
Main Methods:
- Retinoic acid treatment of ACTH-secreting tumor cells, human pituitary ACTH-secreting tumor cells, and small-cell lung cancer cell lines.
- Analysis of transcriptional activity of AP-1, Nur77, Nurr1, and COUP-TFI.
- In vivo studies using experimental ACTH-secreting tumors in nude mice.
Main Results:
- Retinoic acid inhibited transcriptional activity of AP-1, Nur77, and Nurr1, reducing pro-opiomelanocortin transcription and ACTH production in tumor cells.
- COUP-TFI expression in tumor cells blocked retinoic acid's action; COUP-TFI was absent in pituitary Cushing tumors but present in normal corticotrophs.
- Retinoic acid inhibited cell proliferation, induced cell death via caspase-3 activation in ACTH-secreting cells, and reduced corticosterone production in adrenal cells.
Conclusions:
- Retinoic acid demonstrates significant therapeutic potential for Cushing syndrome by inhibiting ACTH and corticosterone production and reducing tumor burden.
- The findings suggest retinoic acid can reverse the endocrine and symptomatic manifestations of experimental Cushing syndrome through multiple mechanisms.