Retinoic acid prevents experimental Cushing syndrome

Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACT H) production by neuroendocrine tumors, which subsequently results in chron ic glucocorticoid excess. We found that retinoic acid inhibits the transcri ptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-s ecreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiom elanocortin transcription and ACTH production. ACTH inhibition was also obs erved in human pituitary ACTH-secreting tumor cells and a small-cell lung c ancer cell line, but not in normal cells. This correlated with the expressi on 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 cel l proliferation and, after prolonged treatment, increased caspase-3 activit y and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. T he antiproliferative action and the inhibition of ACTH and corticosterone p roduced by retinoic acid were confirmed in vivo in experimental ACTH-secret ing tumors in nude mice. Thus, we conclude that the effects of retinoic aci d combine in vivo to reverse the endocrine alterations and symptoms observe d in experimental Cushing syndrome.