title: 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.
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Saito-Hakoda
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yokoyama
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Rehana
authors.initials: R
authors.lastname: Parvin
authors.affiliation: Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Saito-Ito
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Sato
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Naotaka
authors.initials: N
authors.lastname: Kogure
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Ikuma
authors.initials: I
authors.lastname: Fujiwara
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Health Service Center, Kochi University, Kochi, Kochi, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D003480:Cushing Syndrome / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology*; D047488:Retinoid X Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D001552:Benzazepines; D001565:Benzoates; C422175:HX 630; C000608768:PA024 compound; D011743:Pyrimidines; D047488:Retinoid X Receptors; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D015081:2-Naphthylamine