Indomethacin elicits proteasomal dysfunctions develops apoptosis through mitochondrial abnormalities
Indomethacin elicits proteasomal dysfunctions develops apoptosis through mitochondrial abnormalities
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DOI：
10.1002/jcp.26081
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发表时间：
2018-02-01
影响因子：
5.6
通讯作者：
Mishra, Amit
中科院分区：
文献类型：
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作者：
Amanullah, Ayeman;Mishra, Ribhav;Mishra, Amit
非甾体类抗炎药（NSAID）是一类主要通过抑制环氧合酶-2（COX-2）来治疗疼痛、炎症和发烧的药物。有大量研究结果揭示了非甾体抗炎药在癌症治疗中隐藏的关键化疗潜力。然而，非甾体抗炎药作为有效抗肿瘤剂预防癌变的确切机制仍不清楚。在这里，我们发现吲哚美辛（一种众所周知的非甾体抗炎药）会诱导蛋白酶体功能障碍，导致不需要的蛋白质积累、线粒体异常，并相继刺激细胞凋亡。我们观察到吲哚美辛与蛋白酶体的相互作用，并注意到细胞内泛素阳性蛋白大量积累，这可能是由于蛋白酶体活性受到抑制所致。此外，我们还发现吲哚美辛的暴露会导致关键蛋白酶体底物的积累，从而产生严重的线粒体异常并促进细胞中的关键凋亡事件。我们的结果证明了吲哚美辛如何影响正常的蛋白酶体功能并诱导细胞中的线粒体凋亡。这些发现还提高了我们目前对非甾体抗炎药如何在细胞中发挥重要的抗增殖作用的理解。在不久的将来，我们的研究结果可能会提出一种新的可能策略，用于开发特定蛋白酶体抑制剂与其他化学预防抗癌药物的结合。
Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that are mainly used to treat pain, inflammation, and fever via cyclooxygenase-2 (COX-2) inhibition. There are abundant findings that uncover the hidden critical chemotherapeutics potential of NSAIDs in cancer treatment. However, still the precise mechanism by which NSAIDs could be used as an effective anti-tumor agent in the prevention of carcinogenesis is not well understood. Here, we show that indomethacin, a well-known NSAID, induces proteasomal dysfunction that results in accumulation of unwanted proteins, mitochondrial abnormalities, and successively stimulate apoptosis in cells. We observed the interaction of indomethacin with proteasome and noticed the massive accumulation of intracellular ubiquitin-positive proteins, which might be due to the suppression of proteasome activities. Furthermore, we also found that exposure of indomethacin causes the accumulation of critical proteasomal substrates that consequently generate severe mitochondrial abnormalities and prompt up key apoptotic events in cells. Our results demonstrate how indomethacin affects normal proteasomal functions and induces mitochondrial apoptosis in cells. These findings also improve our current understanding of how NSAIDs can exhibit crucial anti-proliferative effects in cells. In near future, our findings may suggest a new possible strategy for the development of specific proteasome inhibitors in conjunction with other chemo-preventive anticancer agents.