CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Changhai Hospital, The Second Military Medical University, Shanghai 200433, China.
EBioMedicine. 2019 Sep;47:65-77. doi: 10.1016/j.ebiom.2019.08.057. Epub 2019 Sep 5.
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.
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.
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.
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.
顺铂耐药仍是非小细胞肺癌（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，尚不清楚 Scribble 是否以及如何参与顺铂相关的细胞死亡，以及 Scribble 如何响应化疗以及在 NSCLC 中的氧化应激过程。
我们使用了两个独立的 NSCLC 样本队列，这些样本来自接受含铂化疗的患者，并在体内进行了异种移植建模。我们分析了 Scribble 与 Nox2 或 Nrf2/PD-L1 之间在体内和体外的相关性，并探讨了 Scribble 在顺铂诱导的 ROS 和细胞凋亡中的作用。
临床分析表明，Scribble 的表达与 NSCLC 患者的临床结果和化疗敏感性呈正相关。Scribble 保护 Nox2 蛋白免受蛋白酶体降解。Scribble 敲低通过依赖 LRR 结构域阻断 Nox2/ROS 和细胞凋亡来诱导顺铂耐药。此外，体内和体外研究表明，Scribble 水平低与 PD-L1 水平高相关，这是通过激活 Nrf2 转录实现的。
我们的研究表明，极性蛋白 Scribble 增加了顺铂诱导的 ROS 生成，有利于 NSCLC 的化疗结果。虽然 Scribble 缺乏倾向于通过 Nox2/ROS 和 Nrf2/PD-L1 导致顺铂耐药，但 Scribble 缺乏诱导的 PD-L1 仍可能在免疫治疗中获益。
国家重点研发计划、中国科学院战略性先导科技专项、国家自然科学基金、中国博士后科学基金。
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