Peroxisome proliferator-activated receptor-γ agonists suppress adrenocortical tumor cell proliferation and induce differentiation
Peroxisome proliferator-activated receptor-γ agonists suppress adrenocortical tumor cell proliferation and induce differentiation
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DOI：
10.1210/jc.2004-1267
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发表时间：
2005-07-01
影响因子：
5.8
通讯作者：
Beuschlein, F
中科院分区：
文献类型：
--
作者：
Betz, MJ;Shapiro, I;Beuschlein, F
内容：噻唑烷二酮类化合物（TZDs）作为过氧化物酶体增殖物激活受体（PPAR）-γ的特异性配体已被应用于2型糖尿病的临床治疗。此外，最近的证据表明，TZDs可能有良好的效果，在治疗各种肿瘤的分化诱导剂。肾上腺皮质癌（ACC）是一种罕见的肿瘤，由于其高度恶性表型且缺乏有效的治疗方案，预后较差。目的：本研究的目的是探讨TZD对肾上腺皮质癌细胞的影响。结果：在所有肾上腺皮质肿瘤（包括ACC）中均可检测到PPAR γ mRNA的表达，表达水平相似。此外，孵育的肾上腺皮质肿瘤细胞系NCI h295与PPAR γ激动剂罗格列酮导致细胞活力下降，细胞增殖减少，细胞凋亡以及类固醇生成增加。在分子水平上，NCI h295细胞在治疗后表达更高水平的ACTH受体（黑皮质素受体-2）mRNA，而细胞周期蛋白E mRNA减少，从而反映了向在体内侵袭性较低的肾上腺皮质肿瘤中发现的表达模式的转变。因此，荧光素酶实验证实了罗格列酮刺激后黑皮质素受体-2的启动子活性增加。与特异性PPAR γ拮抗剂GW 9662共孵育显示TZD诱导的类固醇生成增加受到抑制，而TZD处理后的生长抑制不受GW 9662的影响。结论：TZD处理对NCI h295细胞的表型效应可能与PPAR γ依赖性和非依赖性效应有关。总之，这些数据表明，TZD可能有潜力成为ACC患者分化诱导剂的额外治疗选择。
Context: Thiazolidinediones (TZDs) have been implemented into clinical practice for the treatment of type 2 diabetes mellitus as specific peroxisome proliferator-activated receptor (PPAR)-gamma ligands. Moreover, recent evidence has suggested that TZDs might have favorable effects in the treatment of a variety of tumors as differentiation-inducing agents. Adrenocortical carcinoma (ACC) is a rare tumor entity with poor prognosis due to its highly malignant phenotype and lack of effective treatment options.Objective: The purpose of this study was to investigate effects of TZDs on adrenocortical cancer cells.Results: PPAR gamma mRNA expression was detectable in all adrenocortical tumors including ACCs at similar levels. Furthermore, incubation of the adrenocortical tumor cell line NCI h295 with the PPAR gamma agonist rosiglitazone led to a decrease in cell viability, a decrease of cellular proliferation, and an increase in apoptosis as well as steroidogenesis. On the molecular level, NCI h295 cells expressed higher levels of ACTH receptor (melanocortin receptor-2) mRNA upon treatment, whereas cyclin E mRNA was reduced, thus reflecting a shift toward an expression pattern found in less aggressive adrenocortical tumors in vivo. Accordingly, luciferase experiments confirmed an increased promoter activity for the melanocortin receptor-2 after stimulation with rosiglitazone. Coincubation with the specific PPAR gamma antagonist GW9662 demonstrated the inhibition of TZD-induced increase in steroidogenesis, whereas growth suppression upon TZD treatment was not affected by GW9662.Conclusions: Thus, both PPAR gamma-dependent and PPAR gamma-independent effects of TZD treatment are likely to contribute to the observed phenotypical effects on NCI h295 cells. Taken together, these data indicate that TZDs might have the potential to become an additional treatment option as differentiation-inducing agents in patients with ACC.