Non-steroidal anti-inflammatory drugs inhibit cellular proliferation and upregulate cyclooxygenase-2 protein expression in endometrial cancer cells
Non-steroidal anti-inflammatory drugs inhibit cellular proliferation and upregulate cyclooxygenase-2 protein expression in endometrial cancer cells
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DOI：
10.1111/j.1349-7006.2004.tb02200.x
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发表时间：
2004-11-01
期刊：
影响因子：
5.7
通讯作者：
Tamaya, T
中科院分区：
文献类型：
--
作者：
Gao, JC;Niwa, K;Tamaya, T
我们确定了几种非甾体抗炎药（NSAID），阿司匹林（乙酰水杨酸，阿萨），吲哚美辛和环氧合酶-2（考克斯-2）选择性抑制剂（NS 398）对体外子宫内膜癌细胞的细胞增殖和考克斯-2蛋白表达的调节作用，并研究了它们的作用方式。所有三种NSAID均以时间和浓度依赖性方式显著抑制石川、HEC-1A和AN 3CA子宫内膜癌细胞系的增殖。阿萨和消炎痛通过释放胞浆细胞色素c、激活半胱氨酸蛋白酶-9和-3以及切割聚（ADP-核糖）聚合酶（PARP）来触发所有三个细胞系的细胞凋亡，但NS 398仅在石川细胞中诱导了最低限度的细胞凋亡。阿萨改变了细胞周期分布，G2/M期细胞增多，并诱导Ki-67蛋白的过度表达。阿萨和吲哚美辛均降低Bcl-2和Bcl-xl的蛋白水平，但上调Bax和Bcl-xs的蛋白水平。阿萨和吲哚美辛可上调三种细胞系中考克斯-2蛋白表达和PGE（2）的产生。然而，NS 398并不改变这些细胞中考克斯-2蛋白表达或PGE（2）的产生。这些结果表明，NSAID抑制子宫内膜癌细胞的增殖独立于考克斯-2蛋白表达的降低。细胞色素c依赖性凋亡途径和/或细胞周期阻滞可能有助于这些NSAID的抑制作用。
We determined the effects of several non-steroidal anti-inflammatory drugs (NSAIDs), aspirin (acetylsalicylic acid, ASA), indomethacin and a cyclooxygenase-2 (COX-2)-selective inhibitor (NS398), on cellular proliferation and regulation of COX-2 protein expression in endometrial cancer cells in vitro, and investigated their modes of action. All three NSAIDs markedly inhibited the proliferation of Ishikawa, HEC-1A and AN3CA endometrial cancer cell lines in a time- and concentration-dependent manner. ASA and indomethacin triggered apoptosis in cells of all three lines through release of cytosolic cytochrome c, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP), but NS398 induced minimal apoptosis only in Ishikawa cells. ASA altered the cell cycle distribution, with G2/M phase accumulation of cells, and induced overexpression of Ki-67 protein. Both ASA and indomethacin reduced the protein levels of Bcl-2 and Bcl-xl, but upregulated those of Bax and Bcl-xs. COX-2 protein expression and PGE(2) production were upregulated by ASA and indomethacin in all three cell lines. However, NS398 did not alter COX-2 protein expression or PGE(2) production in these cells. These results indicate that NSAIDs inhibit proliferation of endometrial cancer cells independently of the reduction of COX-2 protein expression. A cytochrome c-dependent apoptotic pathway and/or cell cycle arrest may contribute to the inhibitory effects of these NSAIDs.