Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone

Abstract

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 PPARγ protein/mRNA expression in uterine leiomyomas and to identify the PPARγ induced signaling pathways responsible for the growth inhibition induced by treatment with ciglitizone, a synthetic ligand of PPARγ, 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 PPARγ receptors and that PPARγ ligands may be of potential use for uterine leiomyoma treatment. Key words: uterine leiomyoma; PPARγ; ciglitizone; apoptosis