Dataset Information

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

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.

SUBMITTER: Wang N

PROVIDER: S-EPMC6796531 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Wang Na N Song Lele L Xu Yi Y Zhang Longfu L Wu Yanjun Y Guo Jingyu J Ji Weiwei W Li Li L Zhao Jingya J Zhang Xin X Zhan Lixing L

EBioMedicine 20190905

<h4>Background</h4>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.<h4>Methods</h4 ...[more]

PMID: 31495720

Similar Datasets

Project description:BackgroundRecently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear.MethodsMTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors.ResultsWe showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo.ConclusionOur data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets