Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone
Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone
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DOI：
10.1093/molehr/gam071
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发表时间：
2007-11-01
影响因子：
4
通讯作者：
Cho, Chi-Heum
中科院分区：
文献类型：
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作者：
Nam, Dong-Ho;Ramachandran, Sabarish;Cho, Chi-Heum
核受体PPARs（过氧化物酶体增殖物激活受体）是在多种疾病中发挥重要作用的转录因子。特异性配体对PPARs的激活与几种不同类型的人类癌症的生长抑制有关，但负责这种生长抑制作用的分子机制仍然难以捉摸。本研究的目的是确定子宫平滑肌瘤中PPAR γ蛋白/mRNA表达的分布，并确定负责由ciglitizone（一种PPAR γ的合成配体）治疗诱导的生长抑制的PPAR γ诱导的信号通路，以确定可能影响子宫平滑肌瘤细胞活力和增殖的靶点。对增殖的剂量反应研究发现，子宫平滑肌瘤对西格列酮治疗的抑制作用比正常子宫肌层更敏感。我们还发现，ciglitizone显着刺激基因表达驱动的PPAR反应元件在培养的平滑肌瘤细胞和减少平滑肌瘤细胞的生存相对于对照细胞。西格列酮处理的平滑肌瘤细胞的存活率降低是由于涉及Fas受体介导的凋亡信号级联的机制。这些结果表明，子宫平滑肌瘤的生长和分化可能是通过调节过氧化物酶体增殖物激活受体γ受体和过氧化物酶体增殖物激活受体γ配体可能是潜在的使用子宫平滑肌瘤的治疗。
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 PPAR gamma protein/mRNA expression in uterine leiomyomas and to identify the PPAR gamma induced signaling pathways responsible for the growth inhibition induced by treatment with ciglitizone, a synthetic ligand of PPAR gamma, 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 PPAR gamma receptors and that PPAR gamma ligands may be of potential use for uterine leiomyoma treatment.