Inhibiting DX2-p14/ARF Interaction Exerts Antitumor Effects in Lung Cancer and Delays Tumor Progression
Inhibiting DX2-p14/ARF Interaction Exerts Antitumor Effects in Lung Cancer and Delays Tumor Progression
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DOI：
10.1158/0008-5472.can-15-1025
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发表时间：
2016-08-15
期刊：
影响因子：
11.2
通讯作者：
Park, Bum-Joon
中科院分区：
文献类型：
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作者：
Oh, Ah-Young;Jung, Youn Sang;Park, Bum-Joon
氨酰tRNA合成酶复合物相互作用多功能蛋白2（AIMP 2）剪接变体称为DX 2，由香烟烟雾致癌物诱导，通常在人类肺癌标本中检测到。然而，DX 2在肺癌发生中的作用尚不清楚。在本研究中，我们发现DX 2在人肺癌组织和细胞中的表达是由癌基因诱导的。DX 2通过直接结合和抑制p14/ARF阻止癌基因诱导的细胞凋亡和衰老，并促进耐药性。通过化学筛选，我们确定了SLCB 050，一种新的化合物，在体外和体内阻断DX 2和p14/ARF之间的相互作用。SLCB 050以p14/ARF依赖的方式降低人肺癌细胞，特别是小细胞肺癌细胞的活力。此外，在K-Ras驱动的肺肿瘤发生的小鼠模型中，DX 2的异位表达诱导了小细胞和非小细胞肺癌，这两者都可以被SLCB 050治疗抑制。总之，我们的研究结果显示了DX 2如何促进肺癌进展，以及如何阻止其活性作为治疗DX 2水平升高的肺癌患者的策略。(C)2016年AACR。
The aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) splice variant designated DX2 is induced by cigarette smoke carcinogens and is often detected in human lung cancer specimens. However, the function of DX2 in lung carcinogenesis is obscure. In this study, we found that DX2 expression was induced by oncogenes in human lung cancer tissues and cells. DX2 prevented oncogene-induced apoptosis and senescence and promoted drug resistance by directly binding to and inhibiting p14/ARF. Through chemical screening, we identified SLCB050, a novel compound that blocks the interaction between DX2 and p14/ARF in vitro and in vivo. SLCB050 reduced the viability of human lung cancer cells, especially small cell lung cancer cells, in a p14/ARF-dependent manner. Moreover, in a mouse model of K-Ras-driven lung tumorigenesis, ectopic expression of DX2 induced small cell and non-small cell lung cancers, both of which could be suppressed by SLCB050 treatment. Taken together, our findings show how DX2 promotes lung cancer progression and how its activity may be thwarted as a strategy to treat patients with lung cancers exhibiting elevated DX2 levels. (C) 2016 AACR.