Growth inhibition and differentiation of pancreatic cancer cell lines by PPARγ ligand troglitazone
Growth inhibition and differentiation of pancreatic cancer cell lines by PPARγ ligand troglitazone
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DOI：
10.1097/00006676-200201000-00001
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发表时间：
2002-01-01
期刊：
影响因子：
2.9
通讯作者：
Kiyosawa, K
中科院分区：
文献类型：
--
作者：
Kawa, S;Nikaido, T;Kiyosawa, K
简介：过氧化物酶体增殖物激活受体γ的配体激活目的：我们确定了PPAR γ配体曲格列酮是否抑制胰腺癌细胞的生长，并阐明了潜在的机制，特别关注细胞周期晚期G1期的限制点控制，方法：以9株胰腺癌细胞为研究对象，采用MTT法检测曲格列酮对细胞生长的影响，流式细胞仪检测曲格列酮对细胞周期的影响，Western和北方印迹法检测曲格列酮对G1期晚期细胞周期调控因子的影响，CDK 2激酶检测曲格列酮对G1期晚期细胞周期调控因子的影响，胶原凝胶培养和电镜观察曲格列酮对细胞形态的影响。曲格列酮对六种胰腺癌细胞系的生长抑制表现出有效的剂量-反应效应，在10 LM的浓度下，其被抑制至对照的50%以下。细胞生长抑制与细胞周期G1期阻滞有关，其机制可能是通过上调p21 mRNA和蛋白表达，同时抑制CDK 2激酶活性和Rb蛋白磷酸化水平。p21 mRNA表达上调主要是由于mRNA的稳定。结论：Troglitazone通过上调p21蛋白表达对胰腺癌细胞株具有生长抑制和诱导分化作用，提示激活PPAR γ配体可能成为胰腺癌治疗的新的分子靶点。
Introduction: Ligand activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) results in growth inhibition and differentiation of various cancer cells.Aims: We determined whether the PPAR gamma ligand, troglitazone, inhibits the growth of pancreatic cancer cells and clarified the underlying mechanisms with a special focus on restriction point control of the late G1 phase of the cell cycle,Methodology: Nine pancreatic cancer cell lines were used to study a variety of troglitazone effects on cell growth by MTT assay, on cell cycle by flow cytometry, on cell cycle regulating factors of late G1 phase by Western and Northern blotting and CDK2 kinase assay, and on morphology by collagen get culture and electron-microscopy.Results: Troglitazone showed a potent dose-response effect on the growth inhibition of six pancreatic cancer cell lines, which were suppressed to less than 50% of control at the concentration of 10 LM. The growth inhibition was linked to the G1 phase cell cycle arrest through the upregulation of p21 mRNA and protein expression simultaneously with the inhibition of CDK2 kinase activity and the hypophosphorylation of Rb protein. The upregulation of expression of p21 mRNA was mainly due to stabilization of mRNA. Troglitazone induced significant morphologic changes of duct structure with apoptotic cells in the lumen.Conclusion: Troglitazone had growth inhibitory and differentiation induction effects on the pancreatic cancer cell lines through the upregulation of p21 expression, suggesting that ligand activation of PPAR gamma is a new molecular target for effective therapy against pancreatic cancer.