Retinoic acid prevents experimental Cushing syndrome.
Retinoic acid prevents experimental Cushing syndrome.
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DOI：
10.1172/jci11098
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发表时间：
2001-10
期刊：
影响因子：
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通讯作者：
M. Páez-Pereda;Damián Kovalovsky;Ursula Hopfner;M. Theodoropoulou;U. Pagotto;Eberhard Uhl;Marco Losa-M
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文献类型：
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作者：
M. Páez-Pereda;Damián Kovalovsky;Ursula Hopfner;M. Theodoropoulou;U. Pagotto;Eberhard Uhl;Marco Losa-M
库欣综合征是由神经内分泌肿瘤产生的促肾上腺皮质激素（ACTH）过量引起的，其随后导致慢性糖皮质激素过量。我们发现，视黄酸抑制AP-1和孤儿受体Nur 77和Nurr 1在ACTH分泌肿瘤细胞的转录活性。视黄酸处理导致阿黑皮素原转录和ACTH产生减少。在人垂体促肾上腺皮质激素分泌肿瘤细胞和小细胞肺癌细胞系中也观察到促肾上腺皮质激素抑制，但在正常细胞中未观察到。这与孤儿受体COUP-TFI的表达相关，COUP-TFI在正常促肾上腺皮质激素细胞中发现，但在垂体库欣瘤中未发现。COUP-TFI在ACTH分泌肿瘤细胞中的表达阻断了维甲酸的作用。视黄酸还抑制细胞增殖，并且在长期处理后，增加半胱氨酸蛋白酶-3活性并诱导促肾上腺皮质激素分泌细胞的细胞死亡。在肾上腺皮质细胞中，视黄酸抑制皮质酮的产生和细胞增殖。在裸鼠实验性ACTH分泌肿瘤中证实了维甲酸的抗增殖作用和对ACTH和皮质酮产生的抑制作用。因此，我们得出结论，视黄酸的影响联合收割机在体内逆转内分泌的变化和观察到的实验性库欣综合征的症状。
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.