Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells
Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells
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DOI：
10.1016/j.canlet.2014.12.003
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发表时间：
2015-02-28
期刊：
影响因子：
9.7
通讯作者：
Hong, Yang
中科院分区：
文献类型：
--
作者：
Yang, Lina;Zhou, Yunjiao;Hong, Yang
尽管p53和KRAS的突变以及NF-kappa B信号的激活与肺癌的化疗耐药和肿瘤发生高度相关，但p53、KRAS和NF-kappa B三者之间的相互作用机制尚不清楚。在本研究中，我们首次观察到，在KRAS突变体A549细胞系中，I kappa B α突变体（I kappa B α M）阻断NF-kappa B功能可抑制细胞周期进程、抗凋亡、化疗耐药和肿瘤发生。沉默A549或H358细胞中的p53或KRAS可通过促进或抑制NF-kappa B p65核易位增强或减弱细胞对顺铂和紫杉醇的耐药性。将野生型p53引入无p53肺癌细胞系H1299和H358后，抑制NF-kappa B活性，导致对化疗药物的反应增强。将突变体p53或KRAS-V12传递到A549/I kappa B α M或H1299/p53Wt细胞中，由于NF-kappa B p65的累积核定位，增加了细胞周期进展、抗凋亡、化疗耐药和肿瘤发生，而用NF-kappa B抑制剂PSI 145处理H1299/p53Wt/KRAS-V12则减少了这些作用。因此，我们认为p53缺乏和KRAS突变激活NF-kappa B信号控制化疗耐药和肿瘤发生，p53和KRAS的状态可能是肺癌患者靶向治疗NF-kappa B的考虑因素。2014爱思唯尔爱尔兰有限公司版权所有。
Although mutations of p53 and KRAS and activation of NF-kappa B signaling have been highly associated with chemoresistance and tumorigenesis of lung cancer, the interactive mechanisms between two of p53, KRAS, and NF-kappa B are elusive. In the present study, we first observed that blocking of NF-kappa B function in KRAS mutant A549 cell line with an I kappa B alpha mutant (I kappa B alpha M) inhibited cell cycle progression, anti-apoptosis, chemoresistance, and tumorigenesis. Silencing of p53 or KRAS in A549 or H358 cells either enhanced or attenuated the resistance of cells to cisplatin and taxol through promotion or suppression of the NF-kappa B p65 nuclear translocation. Introduction of a wild type p53 into p53 null lung cancer cell lines H1299 and H358 inhibited NF-kappa B activity, leading to the enhanced response to chemotherapeutic drugs. Delivery of a mutant p53 or KRAS-V12 into A549/I kappa B alpha M or H1299/p53Wt cells increased cell cycle progression, anti-apoptosis, chemoresistance, and tumorigenesis due to the accumulated nuclear localization of NF-kappa B p65, while treatment of H1299/p53Wt/KRAS-V12 with NF-kappa B inhibitor PSI 145 diminished these effects. Thus, we conclude that p53 deficiency and KRAS mutation activate the NF-kappa B signaling to control chemoresistance and tumorigenesis, and that the status of p53 and KRAS may be considered for the targeted therapy against NF-kappa B in lung cancer patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved.