Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis
Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis
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DOI：
10.1038/sj.cdd.4401436
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发表时间：
2004-09-01
影响因子：
12.4
通讯作者：
Mizushima, T
中科院分区：
文献类型：
--
作者：
Tsutsumi, S;Gotoh, T;Mizushima, T
非甾体抗炎药（NSAIDs）诱导的细胞凋亡不仅参与非甾体抗炎药诱导的胃病变的产生，而且参与这些药物的抗肿瘤活性。内质网（ER）应激反应是一种细胞机制，有助于保护内质网免受内质网应激源的影响，并参与内质网应激源诱导的细胞凋亡。在此，我们研究了这种反应与非甾体抗炎药诱导的豚鼠胃粘膜细胞凋亡之间的关系。细胞暴露于吲哚美辛（一种常用的非甾体抗炎药）可诱导GRP78和CHOP（一种参与细胞凋亡的转录因子）。吲哚美辛可激活和/或诱导3个正向调节CHOP表达的因子（ATF6、ATF4和XBP-1）。除吲哚美辛外，非甾体抗炎药（双氯芬酸、布洛芬和塞来昔布）也可引起CHOP。荧光素酶法检测ATF6和CHOP的转录活性发现，吲哚美辛存在时，两者都受到刺激。此外，在培养的豚鼠胃粘膜细胞中，通过表达CHOP的显性阴性形式或CHOP缺陷小鼠的腹膜巨噬细胞，可抑制吲哚美辛诱导的细胞凋亡。这些结果表明内质网应激反应相关蛋白，特别是CHOP，参与了nsaid诱导的细胞凋亡。
Apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs) is involved not only in the production of NSAID-induced gastric lesions but also in the antitumor activity of these drugs. The endoplasmic reticulum (ER) stress response is a cellular mechanism that aids in protecting the ER against ER stressors and is involved in ER stressor-induced apoptosis. Here, we examine the relationship between this response and NSAID-induced apoptosis in cultured guinea-pig gastric mucosal cells. Exposure of cells to indomethacin, a commonly used NSAID, induced GRP78 as well as CHOP, a transcription factor involved in apoptosis. Three factors that positively regulate CHOP expression (ATF6, ATF4 and XBP-1) were activated and/or induced by indomethacin. NSAIDs other than indomethacin (diclofenac, ibuprofen and celecoxib) also induced CHOP. Monitoring of the transcriptional activities of ATF6 and CHOP by luciferase assay revealed that both were stimulated in the presence of indomethacin. Furthermore, indomethacin-induced apoptosis was suppressed in cultured guinea-pig gastric mucosal cells by expression of the dominant-negative form of CHOP, or in peritoneal macrophages from CHOP-deficient mice. These results suggest that ER stress response-related proteins, particularly CHOP, are involved in NSAID-induced apoptosis.