TY - JOUR
T1 - Effects of RXR Agonists on Cell Proliferation/ Apoptosis and ACTH Secretion/Pomc Expression
AU - Saito-Hakoda, Akiko
AU - Uruno, Akira
AU - Yokoyama, Atsushi
AU - Shimizu, Kyoko
AU - Parvin, Rehana
AU - Kudo, Masataka
AU - Saito-Ito, Takako
AU - Sato, Ikuko
AU - Kogure, Naotaka
AU - Suzuki, Dai
AU - Yoshikawa, Takeo
AU - Fujiwara, Ikuma
AU - Kagechika, Hiroyuki
AU - Iwasaki, Yasumasa
AU - Kure, Shigeo
AU - Ito, Sadayoshi
AU - Sugawara, Akira
N1 - Publisher Copyright:
©2015 Saito-Hakoda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958213247&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958213247&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0141960
DO - 10.1371/journal.pone.0141960
M3 - Article
C2 - 26714014
AN - SCOPUS:84958213247
VL - 10
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 12
M1 - 0141960
ER -