TRAP1 regulates proliferation, mitochondrial function, and has prognostic significance in NSCLC.
TRAP1 regulates proliferation, mitochondrial function, and has prognostic significance in NSCLC.
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DOI：
10.1158/1541-7786.mcr-13-0481
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Pezzella F
中科院分区：
文献类型：
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作者：
Agorreta J;Hu J;Liu D;Delia D;Turley H;Ferguson DJ;Iborra F;Pajares MJ;Larrayoz M;Zudaire I;Pio R;Montuenga LM;Harris AL;Gatter K;Pezzella F
肿瘤坏死因子受体相关蛋白1（TRAP 1）是一种线粒体热休克蛋白，与结直肠癌和前列腺癌的耐药性和细胞凋亡保护有关。在此，确定了TRAP 1消融对非小细胞肺癌（NSCLC）中细胞增殖、存活、凋亡和线粒体功能的影响。此外，在NSCLC患者中评估TRAP 1的预后价值。这些结果表明TRAP 1敲低降低了细胞生长和克隆形成细胞存活。此外，TRAP 1下调损害线粒体功能，如ATP产生和线粒体膜电位，如通过TMRM（四甲基罗丹明甲酯）摄取测量的，但它不影响线粒体密度或线粒体形态。TRAP 1沉默对细胞凋亡的影响，通过流式细胞术和免疫印迹表达（裂解：PARP，半胱天冬酶9和半胱天冬酶3）分析是细胞系和上下文依赖性的。最后，通过免疫组化分析确定TRAP 1在NSCLC中表达的预后潜力，其显示TRAP 1高表达与疾病复发风险增加相关（单变量分析，P=0.008;多变量分析，风险比：2.554; 95%CI：1.085-6.012; P=0.03）。总之，这些结果表明TRAP 1影响NSCLC细胞的活力，并且其表达在NSCLC中具有预后性。TRAP 1控制NSCLC增殖、凋亡和线粒体功能，其状态在NSCLC中具有预后潜力。
The tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial heat shock protein that has been related to drug resistance and protection from apoptosis in colorectal and prostate cancer. Here the effect of TRAP1 ablation on cell proliferation, survival, apoptosis and mitochondrial function was determined in non-small cell lung cancer (NSCLC). In addition, the prognostic value of TRAP1 was evaluated in NSCLC patients. These results demonstrate that TRAP1 knockdown reduces cell growth and clonogenic cell survival. Moreover, TRAP1 down-regulation impairs mitochondrial functions such as ATP production and mitochondrial membrane potential as measured by TMRM (tetramethylrhodamine methylester) uptake, but it does not affect mitochondrial density or mitochondrial morphology. The effect of TRAP1 silencing on apoptosis, analyzed by flow cytometry and immunoblot expression (cleaved: PARP, caspase 9, and caspase 3) was cell line and context dependent. Finally, the prognostic potential of TRAP1 expression in NSCLC was ascertained via immunohistochemical analysis which revealed that high TRAP1 expression was associated with increased risk of disease recurrence (univariate analysis, P=0.008; multivariate analysis, hazard ratio: 2.554; 95% CI: 1.085-6.012; P=0.03). In conclusion, these results demonstrate that TRAP1 impacts the viability of NSCLC cells, and that its expression is prognostic in NSCLC. TRAP1 controls NSCLC proliferation, apoptosis and mitochondrial function, and its status has prognostic potential in NSCLC.