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

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...

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Autores principales: Yu, Baodan, Zheng, Lixia, Tang, Huiqin, Wang, Weixin, Lin, Yongping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383048/
https://www.ncbi.nlm.nih.gov/pubmed/34396444
http://dx.doi.org/10.3892/mmr.2021.12349
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author Yu, Baodan
Zheng, Lixia
Tang, Huiqin
Wang, Weixin
Lin, Yongping
author_facet Yu, Baodan
Zheng, Lixia
Tang, Huiqin
Wang, Weixin
Lin, Yongping
author_sort Yu, Baodan
collection PubMed
description 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 IC(25), 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 IC(25), 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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spelling pubmed-83830482021-08-30 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 Mol Med Rep Articles 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 IC(25), 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 IC(25), 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. D.A. Spandidos 2021-10 2021-08-09 /pmc/articles/PMC8383048/ /pubmed/34396444 http://dx.doi.org/10.3892/mmr.2021.12349 Text en Copyright: © Yu et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Yu, Baodan
Zheng, Lixia
Tang, Huiqin
Wang, Weixin
Lin, Yongping
Cucurbitacin B enhances apoptosis in gefitinib resistant non-small cell lung cancer by modulating the miR-17-5p/STAT3 axis
title Cucurbitacin B enhances apoptosis in gefitinib resistant non-small cell lung cancer by modulating the miR-17-5p/STAT3 axis
title_full Cucurbitacin B enhances apoptosis in gefitinib resistant non-small cell lung cancer by modulating the miR-17-5p/STAT3 axis
title_fullStr Cucurbitacin B enhances apoptosis in gefitinib resistant non-small cell lung cancer by modulating the miR-17-5p/STAT3 axis
title_full_unstemmed Cucurbitacin B enhances apoptosis in gefitinib resistant non-small cell lung cancer by modulating the miR-17-5p/STAT3 axis
title_short Cucurbitacin B enhances apoptosis in gefitinib resistant non-small cell lung cancer by modulating the miR-17-5p/STAT3 axis
title_sort cucurbitacin b enhances apoptosis in gefitinib resistant non-small cell lung cancer by modulating the mir-17-5p/stat3 axis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383048/
https://www.ncbi.nlm.nih.gov/pubmed/34396444
http://dx.doi.org/10.3892/mmr.2021.12349
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