Peroxisome proliferator-activated receptor γ-dependent and -independent growth inhibition of gastrointestinal tumour cells
Peroxisome proliferator-activated receptor γ-dependent and -independent growth inhibition of gastrointestinal tumour cells
复制标题
DOI：
10.1111/j.1365-2443.2004.00793.x
复制
发表时间：
2004-11-01
期刊：
影响因子：
2.1
通讯作者：
Kinoshita, Y
中科院分区：
文献类型：
--
作者：
Rumi, MAK;Ishihara, S;Kinoshita, Y
过氧化物酶体增殖体激活受体（PPARgamma）是一种配体激活的转录因子。尽管在表达PPARgamma的人类癌症中，对配体诱导的细胞分化和生长抑制的研究最多，但目前尚不清楚PPARgamma的转录激活是否是生长抑制的主要机制。在这项研究中，我们研究了几种胃肠道肿瘤细胞系中PPARgamma的生长抑制作用与转录激活之间是否存在联系。采用PPRE-luciferase载体，采用报告基因法测定了PPARgamma的转录激活电位，并采用h -3-胸苷结合法研究了在噻唑烷二酮配体、罗格列酮和曲格列酮存在或不存在的情况下，PPARgamma的生长抑制作用。正如预期的那样，在PPARgamma转录激活电位（t.n n， MKN-45和LoVo）阳性的细胞系中，这两种配体都诱导了生长抑制。然而，在其他一些PPARgamma转录激活电位阴性的细胞系（TT、AGS和HCT-15）中，曲格列酮仍然表现出生长抑制作用。施用PPARgamma拮抗剂GW9662并没有逆转曲格列酮的这种生长抑制活性。PPARgamma显性阴性突变体的引入也没有抑制其活性。这些观察结果表明，罗格列酮主要通过PPARgamma的转录激活抑制细胞生长，而曲格列酮可以通过PPARgamma依赖性和非依赖性途径诱导细胞生长。
Peroxisome proliferator-activated receptor gamma (PPARgamma) acts as a ligand-activated transcription factor. Although ligand-induced cellular differentiation and growth inhibition have been mostly studied on human cancers expressing PPARgamma, it is unclear if the transcriptional activation of PPARgamma is the main mechanism of growth inhibition. In this study, we investigated whether there is a link between growth inhibitory effect and transcriptional activation of PPARgamma in several gastrointestinal tumour cell lines. The transcriptional activation potential of PPARgamma was assessed by reporter gene assay employing a PPRE-luciferase vector, and growth inhibitory effect of PPARgamma was investigated by H-3-thymidine incorporation assay, in the presence or absence of thiazolidinedione ligands, rosiglitazone and troglitazone. As expected, in the case of cell lines positive for the transcriptional activation potential of PPARgamma (T.Tn, MKN-45 and LoVo), both the ligands induced growth inhibition. However, in case of some other cell lines negative for the transcriptional activation potential of PPARgamma (TT, AGS and HCT-15), troglitazone still showed a growth inhibitory effect. Administration of the PPARgamma antagonist GW9662 did not reverse this growth inhibitory activity of troglitazone. The introduction of dominant negative mutants of PPARgamma did not suppress the activity either. These observations suggest that while rosiglitazone inhibits cellular growth predominantly through transcriptional activation of PPARgamma, troglitazone can induce it both in PPARgamma-dependent and -independent pathways.