Phosphorylation of Ribosomal Protein S3 and Antiapoptotic TRAF2 Protein Mediates Radioresistance in Non-small Cell Lung Cancer Cells
Phosphorylation of Ribosomal Protein S3 and Antiapoptotic TRAF2 Protein Mediates Radioresistance in Non-small Cell Lung Cancer Cells
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DOI：
10.1074/jbc.m112.385989
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发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
Youn, BuHyun
中科院分区：
文献类型：
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作者：
Yang, Hee Jung;Youn, HyeSook;Youn, BuHyun
放射抵抗被认为是限制放射治疗疗效的主要因素。然而，辐射抗性的确切分子机制尚未得到解释。为了阐明肺癌的放射抵抗机制，我们比较了两种不同放射敏感性的非小细胞肺癌（NSCLC）细胞的放射反应，并鉴定了赋予放射抵抗的关键分子。在放射抗性NSCLC细胞中，电离辐射（IR）分别导致酪蛋白激酶2 α（CK 2 α）和PKC介导的rpS 3和TRAF 2磷酸化，诱导rpS 3-TRAF 2复合物解离和NF-κ B激活，导致促生存基因（cIAP 1、cIAP 2和生存素）显著上调。此外，解离的磷酸化rpS 3易位到细胞核中并与NF-κ B B复合物（p65和p50）结合，有助于p65 DNA结合特性和特异性。然而，在放射敏感性NSCLC细胞中，由于不存在CK 2 α过表达，未检测到IR介导的rpS 3磷酸化。因此，IR诱导的rpS 3-TRAF 2复合物解离、NF-κ B活化和促存活基因表达未出现。综上所述，我们的研究结果揭示了一种新的放射抗性机制，通过rpS 3，TRAF 2和NF-κ B在NSCLC细胞中的功能协调。此外，我们提供了rpS 3作为一种新的TRAF 2结合蛋白的功能的第一个证据，并证明了rpS 3和TRAF 2的磷酸化是NSCLC细胞放射抗性的关键控制点。这些结果表明，rpS 3和TRAF 2的调节与放射治疗相结合，可能对NSCLC的放射抵抗具有较高的药理学治疗效力。
Radioresistance is considered as a main factor restricting efficacy of radiotherapy. However, the exact molecular mechanism of radioresistance has not been explained yet. In this study, to elucidate radioresistance mechanism in lung cancer, we compared radiation responses in two types of non-small cell lung cancer (NSCLC) cells with different radiosensitivity and identified key molecules conferring radioresistance. In radioresistant NSCLC cells, ionizing radiation (IR) led to casein kinase 2 alpha (CK2 alpha)- and PKC-mediated phosphorylation of rpS3 and TRAF2, respectively, which induced dissociation of rpS3-TRAF2 complex and NF-kappa B activation, resulting in significant up-regulation of prosurvival genes (cIAP1, cIAP2, and survivin). Also, dissociated phospho-rpS3 translocated into nucleus and bound with NF-kappa B complex (p65 and p50), contributing to p65 DNA binding property and specificity. However, in radiosensitive NSCLC cells, IR-mediated rpS3 phosphorylation was not detected due to the absence of CK2 alpha overexpression. Consequently, IR-induced rpS3-TRAF2 complex dissociation, NF-kappa B activation, and prosurvival gene expression were not presented. Taken together, our findings revealed a novel radioresistance mechanism through functional orchestration of rpS3, TRAF2, and NF-kappa B in NSCLC cells. Moreover, we provided the first evidence for the function of rpS3 as a new TRAF2-binding protein and demonstrated that phosphorylation of both rpS3 and TRAF2 is a key control point of radioresistance in NSCLC cells. These results suggest that regulation of rpS3 and TRAF2 in combination with radiotherapy could have high pharmacological therapeutic potency for radioresistance of NSCLC.