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 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.

Mechanisms Underlying Metabolic and Neural Defects in Zebrafish and Human Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

“…Embryos were incubated in 25 µ m PPARG antagonist BADGE[28] or agonist 10 µM Ciglitizone[40] at ∼24 hpf until the desired developmental stage.…”

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

“…Therefore, they concluded that PPARγ signaling may lead to inhibition of leiomyoma growth through modulating estrogen signaling. In addition, Nam and colleagues (161) found that leiomyoma cells are more sensitive than myometrium cells to the proliferation-inhibiting effect of ciglitizone, a member of the TZD family of PPARγ ligands. This implies that PPARγ signaling may modulate leiomyoma growth.…”

“…This implies that PPARγ signaling may modulate leiomyoma growth. Finally, modulating this signaling pathway through PPARγ ligands may present a potential therapeutic target (161,162).…”

Curcumin, a nutritional supplement with antineoplastic activity, enhances leiomyoma cell apoptosis and decreases fibronectin expression

“…As a cancer therapy agent, curcumin has molecular function at the transcriptional level (NF-kB, STAT, AP-1, PPAR-g, Egr-1, b-catenin, and Nrf-2 signaling pathways), and has demonstrated efficacy as an inductor of apoptosis in multiple human cancers including skin (45), leukemia (46), colon (47), liver (48), breast (49), lymphoma (50), neuroblastoma (51), pancreatic (52), lung (52), endometrial (53), and ovarian (54). In human leiomyomas, there is evidence of a disruption in apoptosis, resulting in tumor growth (28); and various potential leiomyoma therapies, including gonadotropin-releasing hormone (GnRH) agonists (55), CDB-2914 (56), cetrorelix (57), asoprisnil (58), genestein/TKS050 (59), 2-methoxyestradiol (60), raloxifene (61), and ciglitizone (62), have demonstrated efficacy by regulating apoptosis in leiomyomas. Our results demonstrate that curcumin stimulated a metabolic profile compatible with the induction of apoptosis in human leiomyoma cells.…”