Indomethacin promotes apoptosis in gastric cancer cells through concomitant degradation of Survivin and Aurora B kinase proteins
Indomethacin promotes apoptosis in gastric cancer cells through concomitant degradation of Survivin and Aurora B kinase proteins
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DOI：
10.1007/s10495-014-1002-3
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发表时间：
2014-09-01
期刊：
影响因子：
7.2
通讯作者：
Jadus, Martin R.
中科院分区：
文献类型：
--
作者：
Chiou, Shiun-Kwei;Hoa, Neil;Jadus, Martin R.
定期使用非甾体类抗炎药 (NSAID) 可降低多种癌症的发病率。这些化学预防作用背后的分子机制仍然知之甚少。目前的研究表明，在胃癌细胞中：（1）吲哚美辛治疗增强了染色体过客蛋白、Survivin和Aurora B激酶的降解； (2) 吲哚美辛治疗以细胞周期无关的方式下调 Aurora B 激酶活性； (3) Survivin水平的siRNA敲低促进Aurora B激酶蛋白降解，反之亦然； (4) Survivin的异位过度表达阻止了吲哚美辛治疗对Aurora B激酶水平和活性的降低，反之亦然； (5) siRNA敲低Aurora B激酶水平和AZD1152抑制其活性诱导细胞凋亡，而Aurora B激酶的过表达抑制吲哚美辛诱导的细胞凋亡； (6) 在 KATO III 和 HT-29 细胞以及小鼠胃粘膜中，吲哚美辛治疗可降低 Aurora B 激酶水平，同时降低生存素水平并诱导细胞凋亡。此前尚未探讨过 Aurora B 激酶功能在 NSAID 诱导的细胞凋亡中的作用。因此，该报告通过阐明 Aurora B 激酶在吲哚美辛诱导的细胞凋亡中的重要作用，更好地了解 NSAID 抗癌作用的分子机制。
Regular usage of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced incidence of a variety of cancers. The molecular mechanisms underlying these chemopreventive effects remain poorly understood. This current investigation showed that in gastric cancer cells: (1) Indomethacin treatment enhanced the degradation of chromosomal passenger proteins, Survivin and Aurora B kinase; (2) Indomethacin treatment down-regulated Aurora B kinase activity in a cell cycle-independent fashion; (3) siRNA knockdown of Survivin level promoted Aurora B kinase protein degradation, and vice versa; (4) ectopic overexpression of Survivin blocked reduction of Aurora B kinase level and activity by indomethacin treatment, and vice versa; (5) siRNA knockdown of Aurora B kinase level and AZD1152 inhibition of its activity induced apoptosis, and overexpression of Aurora B kinase inhibited indomethacin-induced apoptosis; (6) indomethacin treatment reduced Aurora B kinase level, coinciding with reduction of Survivin level and induction of apoptosis, in KATO III and HT-29 cells, and in mouse gastric mucosa. A role for Aurora B kinase function in NSAID-induced apoptosis was not previously explored. Thus this report provides better understanding of the molecular mechanisms underlying the anti-cancer effect of NSAIDs by elucidating a significant role for Aurora B kinase in indomethacin-induced apoptosis.