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EBioMedicine. 2019 Sep 5. pii: S2352-3964(19)30580-8. doi: 10.1016/j.ebiom.2019.08.057. [Epub ahead of print]

Loss of Scribble confers cisplatin resistance during NSCLC chemotherapy via Nox2/ROS and Nrf2/PD-L1 signaling.

Author information

1
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.
2
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.
3
Zhongshan Hospital, Fudan University, Shanghai 200032, China.
4
Department of Biology, Chemistry and Environmental Studies, Molloy College, New York 11571, USA.
5
Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: zhang.xin@zc-hospital.sh.cn.
6
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. Electronic address: lxzhan@sibs.ac.cn.

Abstract

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.

KEYWORDS:

Cisplatin sensitivity; NSCLC; Nox2; PD-L1; ROS; Scribble

PMID:
31495720
DOI:
10.1016/j.ebiom.2019.08.057
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