Targeting CREB-binding protein overrides LPS induced radioresistance in non-small cell lung cancer cell lines.
Targeting CREB-binding protein overrides LPS induced radioresistance in non-small cell lung cancer cell lines.
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DOI：
10.18632/oncotarget.25665
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发表时间：
2018-06-22
期刊：
影响因子：
--
通讯作者：
Subtil FSB
中科院分区：
文献类型：
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作者：
Gökyildirim MY;Grandel U;Hattar K;Dahlem G;Schuetz E;Leinberger FH;Eberle F;Sibelius U;Grimminger F;Seeger W;Engenhart-Cabillic R;Dikomey E;Subtil FSB
非小细胞肺癌（NSCLC）的预后非常差，即使用当今最好的治疗方法治疗，通常包括放射治疗。NSCLC经常并发肺部感染，这似乎会损害预后以及治疗，其中潜在的机制仍然未知。本文探讨了细菌脂多糖（LPS）是否能改变肿瘤细胞的放射敏感性。发现LPS诱导辐射抗性，但仅在具有活性TLR-4途径的细胞中。蛋白质组分析显示，LPS结合辐射导致cAMP反应元件结合蛋白（CREB）的强烈磷酸化。特异性抑制剂ICG-001抑制CREB结合蛋白（CBP）不仅消除了LPS诱导的辐射抗性，甚至导致辐射敏感性增加。ICG-001引起的致敏作用可能归因于DNA双链断裂（DSB）修复的减少。结果表明，在NSCLC细胞中，LPS导致CREB依赖性辐射抗性，然而，通过特异性抑制剂ICG-001抑制CBP，其是可逆的。这些结果表明，放射和CBP抑制剂的联合治疗可能会改善患有肺部感染的NSCLC患者的生存率。
Non-small cell lung cancer (NSCLC) has a very poor prognosis even when treated with the best therapies available today often including radiation. NSCLC is frequently complicated by pulmonary infections which appear to impair prognosis as well as therapy, whereby the underlying mechanisms are still not known. It was investigated here, whether the bacterial lipopolysaccharides (LPS) might alter the tumor cell radiosensitivity. LPS were found to induce a radioresistance but solely in cells with an active TLR-4 pathway. Proteome profiling array revealed that LPS combined with irradiation resulted in a strong phosphorylation of cAMP response element-binding protein (CREB). Inhibition of CREB binding protein (CBP) by the specific inhibitor ICG-001 not only abrogated the LPS-induced radioresistance but even led to an increase in radiosensitivity. The sensitization caused by ICG-001 could be attributed to a reduction of DNA double-strand break (DSB) repair. It is shown that in NSCLC cells LPS leads to a CREB dependent radioresistance which is, however, reversible through CBP inhibition by the specific inhibitor ICG-001. These findings indicate that the combined treatment with radiation and CBP inhibition may improve survival of NSCLC patients suffering from pulmonary infections.