TRIP13 overexpression promotes gefitinib resistance in non‑small cell lung cancer via regulating autophagy and phosphorylation of the EGFR signaling pathway

Xiao,Zhangxian; Li,Mingxi; Zhang,Xiaoqian; Rong,Xuezhu; Xu,Hongtao

doi:10.3892/or.2023.8521

TRIP13 overexpression promotes gefitinib resistance in non‑small cell lung cancer via regulating autophagy and phosphorylation of the EGFR signaling pathway

Authors:
- Zhangxian Xiao
- Mingxi Li
- Xiaoqian Zhang
- Xuezhu Rong
- Hongtao Xu
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Affiliations: Department of Pathology, The First Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110122, P.R. China, Department of Pathology, The First Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China
Published online on: March 8, 2023 https://doi.org/10.3892/or.2023.8521
Article Number: 84
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Non‑small cell lung cancer (NSCLC) accounts for the majority of lung cancers and remains the most common cause of cancer‑related death. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR‑TKIs) have been used as first‑line treatment for patients with NSCLC showing EGFR mutations. Unfortunately, drug resistance is a crucial barrier affecting the treatment of patients with NSCLC. Thyroid hormone receptor interactor 13 (TRIP13) is an ATPase that is overexpressed in numerous tumors and is involved in drug resistance. However, whether TRIP13 plays a role in regulating sensitivity to EGFR‑TKIs in NSCLC remains unknown. TRIP13 expression was evaluated in gefitinib‑sensitive (HCC827) and ‑resistant (HCC827GR and H1975) cell lines. The effect of TRIP13 on gefitinib sensitivity was assessed using the MTS assay. The expression of TRIP13 was upregulated or knocked down to determine its effect on cell growth, colony formation, apoptosis and autophagy. Additionally, the regulatory mechanism of TRIP13 on EGFR and its downstream pathways in NSCLC cells were examined using western blotting, immunofluorescence and co‑immunoprecipitation assays. The expression levels of TRIP13 were significantly higher in gefitinib‑resistant than in gefitinib‑sensitive NSCLC cells. TRIP13 upregulation enhanced cell proliferation and colony formation while reducing the apoptosis of gefitinib‑resistant NSCLC cells, suggesting that TRIP13 may facilitate gefitinib resistance in NSCLC cells. In addition, TRIP13 improved autophagy to desensitize gefitinib in NSCLC cells. Furthermore, TRIP13 interacted with EGFR and induced its phosphorylation and downstream pathways in NSCLC cells. The present study demonstrated that TRIP13 overexpression promotes gefitinib resistance in NSCLC by regulating autophagy and activating the EGFR signaling pathway. Thus, TRIP13 could be used as a biomarker and therapeutic target for gefitinib resistance in NSCLC.

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