Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone.
The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors that play important roles in multiple disease conditions. The activation of PPARs by specific ligands is associated with growth suppression of several different types of human cancer, but the molecular mechanism responsible for this growth suppressive effect remains elusive. The aim of this study was to determine the distribution of PPARgamma protein/mRNA expression in uterine leiomyomas and to identify the PPARgamma induced signaling pathways responsible for the growth inhibition induced by treatment with ciglitizone, a synthetic ligand of PPARgamma, in view of identifying targets that could possibly affect the viability and proliferation of uterine leiomyoma cells. Dose-response studies on proliferation found that uterine leiomyoma was more sensitive to inhibition by ciglitizone treatments than normal myometrium. We also found that ciglitizone significantly stimulated gene expression driven by a PPAR-responsive element in cultured leiomyoma cells and reduced the survival of leiomyoma cells relative to the control cells. The reduced survival of ciglitizone treated leiomyoma cells resulted from a mechanism that involved the Fas receptor-mediated apoptosis signaling cascade. These results suggest that uterine leiomyomas growth and differentiation might be modulated through PPARgamma receptors and that PPARgamma ligands may be of potential use for uterine leiomyoma treatment.
Nam
Dong-Ho
DH
Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, 194 Dongsan-Dong, Jung-Ku, Daegu 700-712, South Korea.
Ramachandran
Sabarish
S
Song
Dae-Kyu
DK
Kwon
Kun-Young
KY
Jeon
Dong-Seok
DS
Shin
So-Jin
SJ
Kwon
Sang-Hoon
SH
Cha
Soon-Do
SD
Bae
Insoo
I
Cho
Chi-Heum
CH
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D047495:PPAR gamma; D045162:Thiazolidinediones; D053181:Caspase 8; C039671:ciglitazone