Document Detail


A novel selective progesterone receptor modulator asoprisnil activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated signaling pathway in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.
MedLine Citation:
PMID:  17105846     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CONTEXT: We previously demonstrated that asoprisnil, a selective progesterone receptor modulator, induces apoptosis of cultured uterine leiomyoma cells. This study was conducted to evaluate whether asoprisnil activates TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptotic pathway in cultured uterine leiomyoma and matching myometrial cells. OBJECTIVE AND METHODS: After subculture in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h, cultured cells were stepped down to serum-free conditions for 24 h in the absence or presence of graded concentrations of asoprisnil. The levels of TRAIL signaling molecules and cellular inhibitors of apoptosis protein were assessed by Western blot analysis. RESULTS: TRAIL contents in untreated cultured leiomyoma cells were significantly (P < 0.01) lower compared with those in untreated cultured myometrial cells. There was no difference in death receptor (DR)4 and DR5 contents between the two types of cells. Asoprisnil treatment significantly (P < 0.05) increased TRAIL, DR4, and DR5 contents in cultured leiomyoma cells in a dose-dependent manner with a cleavage of caspase-8, -7, and -3, and decreased X-linked chromosome-linked inhibitor of apoptosis protein contents. In cultured myometrial cells, however, asoprisnil treatment did not affect either TRAIL signaling molecule or cellular inhibitors of apoptosis protein contents. The concomitant treatment with 100 ng/ml P4 significantly (P < 0.05) reversed asoprisnil-induced increase in DR4 and cleaved poly(adenosine 5'-diphosphate-ribose) polymerase contents in cultured leiomyoma cells. CONCLUSIONS: These results suggest that asoprisnil induces apoptosis of cultured leiomyoma cells by activating TRAIL-mediated apoptotic pathway and down-regulating X-linked chromosome-linked inhibitor of apoptosis protein levels in the absence of comparable effects on myometrial cells.
Authors:
Hiroko Sasaki; Noriyuki Ohara; Qin Xu; Jiayin Wang; Deborah A DeManno; Kristof Chwalisz; Shigeki Yoshida; Takeshi Maruo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-11-14
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  92     ISSN:  0021-972X     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-02-07     Completed Date:  2007-03-15     Revised Date:  2008-05-14    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  616-23     Citation Subset:  AIM; IM    
Affiliation:
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
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MeSH Terms
Descriptor/Qualifier:
Adult
Apoptosis / drug effects
Caspase 3 / metabolism
Caspase 7 / metabolism
Caspase 8 / metabolism
Estrenes / pharmacology*
Female
Humans
Inhibitor of Apoptosis Proteins / metabolism
Leiomyoma / metabolism*,  pathology
Middle Aged
Myometrium / cytology
Oximes / pharmacology*
Oxytocics / pharmacology*
Receptors, Progesterone / metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
Receptors, Tumor Necrosis Factor / metabolism
Signal Transduction / drug effects*
TNF-Related Apoptosis-Inducing Ligand / metabolism*
Tumor Cells, Cultured
Uterine Neoplasms / metabolism*,  pathology
X-Linked Inhibitor of Apoptosis Protein / metabolism
Chemical
Reg. No./Substance:
0/Estrenes; 0/Inhibitor of Apoptosis Proteins; 0/Oximes; 0/Oxytocics; 0/Receptors, Progesterone; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/Receptors, Tumor Necrosis Factor; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFRSF10A protein, human; 0/TNFSF10 protein, human; 0/X-Linked Inhibitor of Apoptosis Protein; 0/XIAP protein, human; 0/asoprisnil; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7; EC 3.4.22.-/Caspase 8

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