Biphasic function of GSK3β in gefitinib‑resistant NSCLC with or without EGFR mutations

Li,Junzhe; Wu,Xiayu; Ji,Xiang-Bo; He,Changhao; Xu,Shijie; Xu,Xianhua

doi:10.3892/etm.2023.12187

Biphasic function of GSK3β in gefitinib‑resistant NSCLC with or without EGFR mutations

Authors:
- Junzhe Li
- Xiayu Wu
- Xiang-Bo Ji
- Changhao He
- Shijie Xu
- Xianhua Xu
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Affiliations: Department of Thoracic Surgery, Affiliated Cancer Hospital of Hainan Medical University, Haikou, Hainan 570312, P.R. China, Department of Pathology, Affiliated Cancer Hospital of Hainan Medical University, Haikou, Hainan 570312, P.R. China, Medical Research Center, Affiliated Cancer Hospital of Hainan Medical University, Haikou, Hainan 570312, P.R. China
Published online on: September 4, 2023 https://doi.org/10.3892/etm.2023.12187
Article Number: 488
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs), such as gefitinib, are effective in the treatment of non‑small cell lung cancer (NSCLC) harboring EGFR mutations. However, the mechanism underlying acquired resistance to EGFR‑TKIs remains largely unknown. Therefore, the present study generated gefitinib‑resistant PC‑9 (PC‑9G) cells, which were revealed to be more resistant to gefitinib‑induced reductions in proliferation, migration and invasion, and increases in apoptosis, and had no detectable EGFR mutations compared with the control PC‑9 cell line. In addition, the present study performed genome‑wide transcriptomic analysis of differentially expressed genes between PC‑9 and PC‑9G cell lines. Cell proliferation, colony formation, invasion, migration and flow cytometry analyses were also performed. The genome‑wide transcriptomic analysis revealed that glycogen synthase kinase 3β (GSK3β) was downregulated in PC‑9G cells compared with that in PC‑9 cells. Furthermore, GSK3β overexpression increased the proliferation, migration and invasion of PC‑9 and H1975 gefitinib‑resistant cells. Conversely, overexpression of GSK3β suppressed the proliferation, migration and invasion of PC‑9G cells. Furthermore, AKT inhibition reduced the proliferation, migration and invasion, and induced the apoptosis of PC‑9, PC‑9G and H1975 cells, the effects of which were reversed following AKT activation; notably, the tumor suppressor function of GSK3β was inconsistent with the tumor promotor role of the AKT pathway in PC‑9G cells without EGFR mutation. The present study may provide novel insights into the distinctive role of GSK3β in gefitinib‑resistant NSCLC with or without EGFR mutations, suggesting that a more detailed investigation on GSK3β as a therapeutic target for gefitinib‑resistant NSCLC may be warranted.

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