Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression

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.

Gene expression profiling in human corticotroph tumours reveals distinct, neuroendocrine profiles

“…Interestingly, although POMC is obviously significantly expressed in all specimens, it proved to be overexpressed together with the POMC‐processing co‐adjuvator SCG5 in specimens grouping in cluster B compared to those in clusters A and C. Increased expression of genes involved in other pituitary tumours or ACTH‐secreting neuroendocrine tumours, most notably NOTCH3 , PITX1, LGALS3 and NGRN , was also observed in cluster B. Furthermore, adenomas in this cluster overexpressed the retinoid X receptor beta gene ( RXRB ), thus confirming possibly greater sensitivity to RXR agonists in selected adenomas. TIMP1 (tissue metallopeptidase inhibitor 1) was also overexpressed in cluster B adenomas, which is an interesting result given the recent reports on matrix metalloproteinase‐9 and TIMP1 itself in corticotroph adenomas.…”

“…With regard to genes overexpressed in cluster B compared to the other 2 clusters, we observed overexpression of the POMC gene itself, as well as of SCG5 , which encodes for secretogranin 5 (also known as neuroendocrine protein 7B2) associated with prohormone convertase 2 activation . Furthermore, genes involved in neuroendocrine tumours (eg, NOTCH3 , LGALS3, PITX1 and NGRN ) were also overexpressed in cluster B compared to clusters A and C. Additional genes of interest to corticotroph adenoma pathophysiology were RXRB and TIMP1 in view of their links to retinoic acid sensitivity and matrix metalloproteinase, respectively . Given the number of genes overexpressed in this cluster, we could perform functional analysis and detected significant enrichment for 123 genes.…”

Heme oxygenase-1 protects airway epithelium against apoptosis by targeting the proinflammatory NLRP3–RXR axis in asthma

“…In addition, RXR␣/␤/␥ participates in the induction of cell apoptosis. It has been reported that RXR␣/␤/␥ agonist (retinoic acid) induces apoptosis of tumor cells by activation of both inducible and endothelial nitric-oxide synthase and production of apoptogenic NO (22,23). Because RXR alone and in combination with other nuclear hormone receptors also promotes Th2 differentiation (18), we wondered whether RXR could be exploited to block airway epithelium apoptosis in asthma.…”

Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

“…In support of this concept, the synthetic RARα/β agonist Am80 up-regulated POMC gene transcription by increasing NeuroD1 and Tpit expression [53] (Table 1). These apparent contradictory actions of RAR activation to either stimulate or inhibit POMC transcription could be explained by involvement of an RXR homodimer or permissive heterodimer that mediates these complex and mixed RXR/RAR actions [54,55].…”