Cucurbitacin B enhances apoptosis in gefitinib resistant non‑small cell lung cancer by modulating the miR‑17‑5p/STAT3 axis

Yu,Baodan; Zheng,Lixia; Tang,Huiqin; Wang,Weixin; Lin,Yongping

doi:10.3892/mmr.2021.12349

October-2021 Volume 24 Issue 4

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October-2021 Volume 24 Issue 4

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Article Open Access

Cucurbitacin B enhances apoptosis in gefitinib resistant non‑small cell lung cancer by modulating the miR‑17‑5p/STAT3 axis

Authors:
- Baodan Yu
- Lixia Zheng
- Huiqin Tang
- Weixin Wang
- Yongping Lin
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Affiliations: Department of Laboratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China, Department of Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China

Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 710
|
Published online on: August 9, 2021

https://doi.org/10.3892/mmr.2021.12349
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Abstract

Tyrosine kinase inhibitors, such as gefitinib, are currently widely used as targeted therapeutics for non‑small cell lung cancer (NSCLC). Although drug resistance has become a major obstacle to successful treatment, mechanisms underlying resistance to gefitinib remain unclear. Therefore, the present study aimed to investigate the impact of adjunctive cucurbitacin B (CuB) on gefitinib resistance (GR) in the PC9 cell line, including identifying underlying mechanisms. Reverse transcription‑quantitative PCR demonstrated significant downregulation of microRNA (miR)‑17‑5p expression in GR PC9 cells (PC9/GR), and this could be reversed by CuB. During combination treatment with CuB and gefitinib at IC25, PC9/GR cell proliferation was downregulated, and apoptosis was upregulated. The presence of a miR‑17‑5p inhibitor negated the effects of CuB and gefitinib, whereas the presence of a miR‑17‑5p mimic enhanced them. Luciferase assays demonstrated that the hypothetical target gene, signal transducer and activator of transcription 3 (STAT3), was directly targeted by miR‑17‑5p. Moreover, significant elevation of the STAT3 protein and phosphorylation levels in PC9/GR cells was reversed by the addition of CuB, despite a lack of change in STAT3 transcription level. During combined treatment with CuB and gefitinib at IC25, the STAT3 protein expression was negatively associated with the expression of miR‑17‑5p. Overexpression of STAT3 increased proliferation and decreased apoptosis and the protein levels of apoptosis‑related factors cleaved caspase‑3 and cleaved caspase‑9 of PC9/GR cells. Findings indicated that STAT3 protein and phosphorylation levels became elevated in response to gefitinib, and that CuB‑induced miR‑17‑5p expression led to STAT3 degradation, thereby ameliorating GR. In summary, CuB reduced the proliferation of GR PC9 cells by modulating the miR‑17‑5p/STAT3 axis, and may represent a promising potential novel strategy for the reversal of GR.

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Medicine International

Cucurbitacin B enhances apoptosis in gefitinib resistant non‑small cell lung cancer by modulating the miR‑17‑5p/STAT3 axis

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