Aspirin enhances TRAIL-induced apoptosis via regulation of ERK1/2 activation in human cervical cancer cells
Aspirin enhances TRAIL-induced apoptosis via regulation of ERK1/2 activation in human cervical cancer cells
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DOI：
10.1016/j.bbrc.2012.06.067
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发表时间：
2012-07-20
影响因子：
3.1
通讯作者：
Jang, Young-Ju
中科院分区：
文献类型：
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作者：
Im, Se-Ran;Jang, Young-Ju
肿瘤坏死因子相关凋亡诱导配体（TRAIL）触发肿瘤特异性凋亡。然而，一些肿瘤和癌细胞系对TRAIL具有耐药性。本研究探讨了非甾体抗炎药阿司匹林对人宫颈癌细胞对TRAIL致敏的影响及其作用机制。通过乳酸脱氢酶（LDH）测定和细胞周期亚g1期分析，阿司匹林和TRAIL联合治疗可显著增强凋亡细胞死亡。两种药物共同激活了几种半胱天冬酶和线粒体信号通路。TRAIL单独处理的细胞中Mcl-1蛋白水平升高，细胞外信号相关激酶（ERK）1/2被激活，而联合处理显著抑制ERK1/2的激活，下调Mcl-1蛋白水平。ERK1/2激活抑制剂PD98059也增强了trail诱导的细胞凋亡。PD98059与TRAIL联合处理可激活caspases和线粒体通路，下调Mcl-1水平。这些结果表明，通过抑制ERK1/2的激活，阿司匹林预处理可以使癌细胞对trail诱导的凋亡增敏。这些发现为进一步探索这种联合方法在治疗包括宫颈癌在内的癌症中的潜在应用提供了基础。(C) 2012爱思唯尔公司版权所有。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers tumor-specific apoptosis. However, some tumors and cancer cell lines are resistant to TRAIL Here, the effect of the non-steroidal anti-inflammatory drug aspirin on sensitization of human cervical cancer cells to TRAIL and the underlying mechanism(s) of the effect were explored. Combination treatment with aspirin and TRAIL markedly enhanced apoptotic cell death, as assessed by lactate dehydrogenase (LDH) assay and analysis of cell cycle sub-G1 phase. The two agents together activated the several caspases and mitochondrial signaling pathway. Whereas Mcl-1 protein level was increased and extracellular signal-related kinase (ERK)1/2 was activated in cells treated with TRAIL alone, combination treatment dramatically inhibited ERK1/2 activation and down-regulated Mcl-1 protein level. An inhibitor of ERK1/2 activation, PD98059, also augmented TRAIL-induced apoptosis. Combination treatment with PD98059 and TRAIL showed the activation of caspases and mitochondrial pathway, and the down-regulation of Mcl-1 level. These results suggest that cancer cells can be sensitized to TRAIL-induced apoptosis by pre-treatment with aspirin via suppression of ERK1/2 activation. These findings provide a basis for further exploring the potential applications of this combination approach for the treatment of cancer, including cervical cancer. (C) 2012 Elsevier Inc. All rights reserved.