Loss of Scribble confers cisplatin resistance during NSCLC chemotherapy via Nox2/ROS and Nrf2/PD-L1 signaling
Loss of Scribble confers cisplatin resistance during NSCLC chemotherapy via Nox2/ROS and Nrf2/PD-L1 signaling
复制标题
Scribble 的缺失通过 Nox2/ROS 和 Nrf2/PD-L1 信号传导在 NSCLC 化疗期间赋予顺铂耐药性
DOI：
10.1016/j.ebiom.2019.08.057
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发表时间：
2019-09-01
期刊：
影响因子：
11.1
通讯作者：
Zhan, Lixing
中科院分区：
文献类型：
--
作者：
Wang, Na;Song, Lele;Zhan, Lixing
背景：顺铂耐药仍然是非小细胞肺癌（NSCLC）成功治疗的主要临床障碍。Scribble有助于ROS诱导的炎症，顺铂升高的毒性活性氧（ROS）促进细胞死亡。然而，它是未知的是否以及如何参与的顺铂相关的细胞死亡和基本机制的Scribble在化疗和氧化stressinNSCLC.Methods的过程中：我们使用了两个独立的队列的NSCLC样本来自含铂化疗和异种移植模型治疗的患者在体内。我们分析了Scribble与Nox 2或Nrf 2/PD-L1在体内和体外的相关性，并探讨了Scribble在顺铂诱导的ROS和凋亡中的作用。Scribble保护Nox 2蛋白免于蛋白酶体降解。Scribble基因敲低通过阻断Nox 2/ROS和LRR依赖性凋亡诱导顺铂耐药。此外，低水平的Scribble与高水平的PD-L1通过激活Nrf 2的转录在体内和体外interpretations.Interpretations：我们的研究表明，极性蛋白Scribble增加顺铂诱导的活性氧产生，是有益的化疗结果在NSCLC。虽然Scribble缺陷倾向于通过Nox 2/ROS和Nrf 2/PD-L1导致顺铂耐药，但Scribble缺陷诱导的PD-L1仍有可能在免疫治疗中获益。基金：国家重点研发计划、中国科学院战略重点研究计划、国家自然科学基金、中国博士后科学基金。(c)2019作者由爱思唯尔公司出版。这是一篇开放获取的文章，获得了CC BY-NC-ND许可证（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Background: Cisplatin resistance remains a major clinical obstacle to the successful treatment of non-small cell lung cancer (NSCLC). Scribble contributes to ROS-induced inflammation and cisplatin-elevated toxic reactive oxygen species (ROS) promotes cell death. However, it is unknown whether and how Scribble is involved in the cisplatin-related cell death and the underlying mechanism of Scribble in response to chemotherapies and in the process of oxidative stress in NSCLC.Methods: We used two independent cohorts of NSCLC samples derived from patients treated with platinum-containing chemotherapy and xenograft modeling in vivo. We analyzed the correlation between Scribble and Nox2 or Nrf2/PD-L1 both in vivo and in vitro, and explored the role of Scribble in cisplatin-induced ROS and apoptosis.Findings: Clinical analysis revealed that Scribble expression positively correlated with clinical outcomes and chemotherapeutic sensitivity in NSCLC patients. Scribble protected Nox2 protein from proteasomal degradation. Scribble knockdown induced cisplatin resistance by blocking Nox2/ROS and apoptosis in LRR domain-dependent manner. In addition, low levels of Scribble correlated with high levels of PD-L1 via activation of Nrf2 transcription in vivo and in vitro.Interpretations: Our study revealed that polarity protein Scribble increased cisplatin-induced ROS generation and is beneficial to chemotherapeutic outcomes in NSCLC. Although Scribble deficiency tends to lead to cisplatin resistance by Nox2/ROS and Nrf2/PD-L1, it is still possible that Scribble deficiency-induced PD-L1 may yield benefits in immunotherapy.Fund: National Key R&D Program of China, Strategic Priority Research Program of the Chinese Academy of Sciences, National Natural Science Foundation of China, China Postdoctoral Science Foundation. (c) 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).