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Knockdown of PLAT enhances the anticancer effect of gefitinib in non-small cell lung cancer

BACKGROUND: Tyrosine kinase inhibitors (TKIs), such as gefitinib, are widely used as standard treatments for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, the subsequent inevitable drug resistance has become a major challenge in clinical...

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Autores principales: Yan, Mengnan, Wang, Wei, Zhou, Jian, Chang, Meijia, Peng, Wenjun, Zhang, Ge, Li, Jing, Li, Huayin, Bai, Chunxue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139041/
https://www.ncbi.nlm.nih.gov/pubmed/32274137
http://dx.doi.org/10.21037/jtd.2019.12.106
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author Yan, Mengnan
Wang, Wei
Zhou, Jian
Chang, Meijia
Peng, Wenjun
Zhang, Ge
Li, Jing
Li, Huayin
Bai, Chunxue
author_facet Yan, Mengnan
Wang, Wei
Zhou, Jian
Chang, Meijia
Peng, Wenjun
Zhang, Ge
Li, Jing
Li, Huayin
Bai, Chunxue
author_sort Yan, Mengnan
collection PubMed
description BACKGROUND: Tyrosine kinase inhibitors (TKIs), such as gefitinib, are widely used as standard treatments for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, the subsequent inevitable drug resistance has become a major challenge in clinical treatment. The aim of this study was to investigate the role of tissue-type plasminogen activator (PLAT) in gefitinib resistance in NSCLC. METHODS: The function of PLAT was determined using gefitinib-resistant cells and a nude mouse model. The gene knockdown was achieved by Lentivirus based RNA silence technique. Expression of relevant genes and proteins, cell viability, proliferation, apoptosis, cell cycle, reactive oxygen species levels, mitochondrial membrane potential and differential gene expression was detected by RT-qPCR, western blot, cell counting kit-8 assay, EdU incorporation, flow cytometry, JC-1 dye assay and complementary DNA arrays. The effects of PLAT knockdown on tumorigenesis was analyzed in vivo. RESULTS: Gefitinib-resistant cells expressed higher levels of PLAT and that knockdown of PLAT in resistant cells restored gefitinib sensitivity. Tumor proliferation was limited in vivo following PLAT knockdown. Moreover, PLAT knockdown affected mitochondrial function, caused caspase activation and cell cycle arrest, and activated TNF-α signaling, leading to apoptosis of gefitinib-resistant PC9 cells. CONCLUSIONS: Our results suggest that PLAT reduces apoptosis of NSCLC cells and knockdown of PLAT enhances anticancer effect of gefitinib by upregulating TNF-α signaling.
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spelling pubmed-71390412020-04-09 Knockdown of PLAT enhances the anticancer effect of gefitinib in non-small cell lung cancer Yan, Mengnan Wang, Wei Zhou, Jian Chang, Meijia Peng, Wenjun Zhang, Ge Li, Jing Li, Huayin Bai, Chunxue J Thorac Dis Original Article BACKGROUND: Tyrosine kinase inhibitors (TKIs), such as gefitinib, are widely used as standard treatments for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, the subsequent inevitable drug resistance has become a major challenge in clinical treatment. The aim of this study was to investigate the role of tissue-type plasminogen activator (PLAT) in gefitinib resistance in NSCLC. METHODS: The function of PLAT was determined using gefitinib-resistant cells and a nude mouse model. The gene knockdown was achieved by Lentivirus based RNA silence technique. Expression of relevant genes and proteins, cell viability, proliferation, apoptosis, cell cycle, reactive oxygen species levels, mitochondrial membrane potential and differential gene expression was detected by RT-qPCR, western blot, cell counting kit-8 assay, EdU incorporation, flow cytometry, JC-1 dye assay and complementary DNA arrays. The effects of PLAT knockdown on tumorigenesis was analyzed in vivo. RESULTS: Gefitinib-resistant cells expressed higher levels of PLAT and that knockdown of PLAT in resistant cells restored gefitinib sensitivity. Tumor proliferation was limited in vivo following PLAT knockdown. Moreover, PLAT knockdown affected mitochondrial function, caused caspase activation and cell cycle arrest, and activated TNF-α signaling, leading to apoptosis of gefitinib-resistant PC9 cells. CONCLUSIONS: Our results suggest that PLAT reduces apoptosis of NSCLC cells and knockdown of PLAT enhances anticancer effect of gefitinib by upregulating TNF-α signaling. AME Publishing Company 2020-03 /pmc/articles/PMC7139041/ /pubmed/32274137 http://dx.doi.org/10.21037/jtd.2019.12.106 Text en 2020 Journal of Thoracic Disease. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Original Article
Yan, Mengnan
Wang, Wei
Zhou, Jian
Chang, Meijia
Peng, Wenjun
Zhang, Ge
Li, Jing
Li, Huayin
Bai, Chunxue
Knockdown of PLAT enhances the anticancer effect of gefitinib in non-small cell lung cancer
title Knockdown of PLAT enhances the anticancer effect of gefitinib in non-small cell lung cancer
title_full Knockdown of PLAT enhances the anticancer effect of gefitinib in non-small cell lung cancer
title_fullStr Knockdown of PLAT enhances the anticancer effect of gefitinib in non-small cell lung cancer
title_full_unstemmed Knockdown of PLAT enhances the anticancer effect of gefitinib in non-small cell lung cancer
title_short Knockdown of PLAT enhances the anticancer effect of gefitinib in non-small cell lung cancer
title_sort knockdown of plat enhances the anticancer effect of gefitinib in non-small cell lung cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139041/
https://www.ncbi.nlm.nih.gov/pubmed/32274137
http://dx.doi.org/10.21037/jtd.2019.12.106
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