Indomethacin induces cellular morphological change and migration via epithelial-mesenchymal transition in A549 human lung cancer cells: A novel cyclooxygenase-inhibition-independent effect
Indomethacin induces cellular morphological change and migration via epithelial-mesenchymal transition in A549 human lung cancer cells: A novel cyclooxygenase-inhibition-independent effect
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DOI：
10.1016/j.bcp.2011.07.096
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发表时间：
2011-12-01
影响因子：
5.8
通讯作者：
Murayama, Toshihiko
中科院分区：
文献类型：
--
作者：
Kato, Tomoko;Fujino, Hiromichi;Murayama, Toshihiko
环氧化酶（考克斯）-2及其代谢产物前列腺素E-2（PGE（2））的水平在结肠癌和包括肺癌在内的其他癌症中经常升高。非甾体抗炎药被认为通过抑制考克斯-2减少PGE 2的生物合成，对这些疾病具有化学预防作用。尽管考克斯-2/PGE（2）通路可能直接影响肺癌的发生，但一些基于人群的NSAID队列研究显示，其没有显著的保护作用。在这项研究中，使用人非小细胞肺癌A549细胞，我们研究了吲哚美辛，一种有效的NSAID，对肺癌细胞的生长和运动的影响。除了抑制PGE 2的产生和细胞生长，吲哚美辛引起剧烈的形态学变化与应力纤维的损失在时间和剂量依赖性的方式。有趣的是，当细胞用阿司匹林或双氯芬酸（两种其他NSAID）处理时，没有观察到吲哚美辛引起的细胞形状变化，尽管所用浓度足以抑制PGE 2产生。吲哚美辛诱导的A549细胞的形态学变化伴随着减少的粘附分子E-钙粘蛋白和基底层的一个组成部分，胶原IV，以及增加的胶原酶，基质金属蛋白酶-9的活性。此外，吲哚美辛诱导的形状变化导致通过调节过氧化物酶体增殖物激活受体γ增强运动性。吲哚美辛的双重作用，抑制细胞生长和增强迁移，在一定程度上解释了使用这种NSAID治疗肺癌的困难。(C)2011 Elsevier Inc. All rights reserved.
Levels of cyclooxygenase (COX)-2 and its metabolite prostaglandin E-2 (PGE(2)) are frequently increased in colon cancer and other cancers including lung cancer. Non-steroidal anti-inflammatory drugs are considered to have chemo-preventive effects on these diseases by reducing the biosynthesis of PGE2 via their inhibition of COX-2. Although the COX-2/PGE(2) pathway may directly impact on lung carcinogenesis, some population-based cohort studies of NSAIDs showed no significant protective effects. In this study, using human non-small-cell lung cancer A549 cells, we examined the effects of indomethacin, a potent NSAID, on the growth and motility of lung cancer cells. Besides inhibiting PGE2 production and cellular growth, indomethacin caused drastic morphological changes with a loss of stress fibers in a time- and dose-dependent manner. Interestingly, the change in cellular shape caused by indomethacin was not seen when the cells were treated with aspirin or diclofenac, two other NSAIDs, despite the concentrations used being sufficient to inhibit PGE2 production. The indomethacin-induced morphological changes in A549 cells were accompanied by a reduction in levels of the adhesion molecule E-cadherin and a component of basal lamina, collagen IV, as well as an increase in the activity of a collagenase, matrix metalloprotease-9. Furthermore, indomethacin-induced shape changes resulted in enhanced motility via regulation of peroxisome proliferator-activated receptor gamma. The dual effects of indomethacin, inhibition of cellular growth and enhancement of migration, would explain, to some extent, the difficulty in using this NSAID for lung cancer therapy. (C) 2011 Elsevier Inc. All rights reserved.