Abstract
Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing’s disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we examined the effects of synthetic RXR pan-agonists HX630 and PA024 on the proliferation, apoptosis, ACTH secretion, and pro-opiomelanocortin (Pomc) gene expression of murine pituitary corticotroph tumor AtT20 cells. We demonstrated that both RXR agonists induced apoptosis dose-dependently in AtT20 cells, and inhibited their proliferation at their higher doses. Microarray analysis identified a significant gene network associated with caspase 3 induced by high dose HX630. On the other hand, HX630, but not PA024, inhibited Pomc transcription, Pomc mRNA expression, and ACTH secretion dose-dependently. Furthermore, we provide new evidence that HX630 negatively regulates the Pomc promoter activity at the transcriptional level due to the suppression of the transcription factor Nur77 and Nurr1 mRNA expression and the reduction of Nur77/Nurr1 heterodimer recruiting to the Pomc promoter region. We also demonstrated that the HX630-mediated suppression of the Pomc gene expression was exerted via RXRα. Furthermore, HX630 inhibited tumor growth and decreased Pomc mRNA expression in corticotroph tumor cells in female nude mice in vivo. Thus, these results indicate that RXR agonists, especially HX630, could be a new therapeutic candidate for Cushing’s disease.
Highlights
Cushing’s disease is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland, or rarely corticotroph hyperplasia, and is the most frequent cause of endogenous hypercortisolism
We examined the effects of retinoid X receptor (RXR) agonists on AtT20 cell proliferation using a WST-8 assay after incubation with various concentrations of agonists for 96 hr
We examined the effects of RXR agonists on the apoptosis of AtT20 cells by activated caspase assay
Summary
Cushing’s disease is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland, or rarely corticotroph hyperplasia, and is the most frequent cause of endogenous hypercortisolism. The risk of recurrence of Cushing’s disease reaches 20– 25% at 10 years after surgery [1]. Radiation therapy is considered as a second-line option for patients with persistent and/or recurrent Cushing’s disease. It has problems, including the delay of therapeutic effect or the risk of secondary hypopituitarism. Several medical therapies have been evaluated for Cushing’s disease, including somatostatin analogues, dopamine agonists, cyproheptadine, and sodium valproate, the effects of these drugs are limited, and medical therapies are not yet considered as a standard therapy [2]. The development of an effective and safe medical therapy is urgently required
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