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Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation
Drug resistance can notably restrict clinical applications of gefitinib that is a commonly used EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). The attempts in exploring novel drug targets and reversal strategies are still needed, since gefitinib resistance has no...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100583/ https://www.ncbi.nlm.nih.gov/pubmed/33967759 http://dx.doi.org/10.3389/fphar.2021.625289 |
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author | Jiang, Yuhong Zhuo, Xin Fu, Xiujuan Wu, Yue Mao, Canquan |
author_facet | Jiang, Yuhong Zhuo, Xin Fu, Xiujuan Wu, Yue Mao, Canquan |
author_sort | Jiang, Yuhong |
collection | PubMed |
description | Drug resistance can notably restrict clinical applications of gefitinib that is a commonly used EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). The attempts in exploring novel drug targets and reversal strategies are still needed, since gefitinib resistance has not been fully addressed. Protease-activated receptor 2 (PAR2), a G protein-coupled receptor, possesses a transactivation with EGFR to initiate a variety of intracellular signal transductions, but there is a lack of investigations on the role of PAR2 in gefitinib resistance. This study established that protease-activated receptor 2 (PAR2), actively participated in NSCLC resistant to gefitinib. PAR2 expression was significantly up-regulated when NSCLC cells or tumor tissues became gefitinib resistance. PAR2 inhibition notably enhanced gefitinib to modulate EGFR transactivation, cell viability, migration and apoptosis in gefitinib-sensitive and-resistant NSCLC cells, suggesting its reversal effects in gefitinib resistance. Meanwhile, the combination of a PAR2 inhibitor (P2pal-18S) and gefitinib largely blocked ERK phosphorylation and epithelial-mesenchymal transition (EMT) compared to gefitinib alone. Importantly, we probed its underlying mechanism and uncovered that PAR2 blockade sensitized gefitinib and reversed its resistance mainly via β-arrestin-EGFR-ERK signaling axis. These effects of PAR2 inhibition were further confirmed by the in vivo study which showed that P2pal-18S reactivated gefitinib to inhibit tumor growth via restricting ERK activation. Taken together, this study could not only reveal a new mechanism of receptor-mediated transactivation to modulate drug resistance, but also provide a novel drug target and direction for overcoming gefitinib resistance in NSCLC. |
format | Online Article Text |
id | pubmed-8100583 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81005832021-05-07 Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation Jiang, Yuhong Zhuo, Xin Fu, Xiujuan Wu, Yue Mao, Canquan Front Pharmacol Pharmacology Drug resistance can notably restrict clinical applications of gefitinib that is a commonly used EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). The attempts in exploring novel drug targets and reversal strategies are still needed, since gefitinib resistance has not been fully addressed. Protease-activated receptor 2 (PAR2), a G protein-coupled receptor, possesses a transactivation with EGFR to initiate a variety of intracellular signal transductions, but there is a lack of investigations on the role of PAR2 in gefitinib resistance. This study established that protease-activated receptor 2 (PAR2), actively participated in NSCLC resistant to gefitinib. PAR2 expression was significantly up-regulated when NSCLC cells or tumor tissues became gefitinib resistance. PAR2 inhibition notably enhanced gefitinib to modulate EGFR transactivation, cell viability, migration and apoptosis in gefitinib-sensitive and-resistant NSCLC cells, suggesting its reversal effects in gefitinib resistance. Meanwhile, the combination of a PAR2 inhibitor (P2pal-18S) and gefitinib largely blocked ERK phosphorylation and epithelial-mesenchymal transition (EMT) compared to gefitinib alone. Importantly, we probed its underlying mechanism and uncovered that PAR2 blockade sensitized gefitinib and reversed its resistance mainly via β-arrestin-EGFR-ERK signaling axis. These effects of PAR2 inhibition were further confirmed by the in vivo study which showed that P2pal-18S reactivated gefitinib to inhibit tumor growth via restricting ERK activation. Taken together, this study could not only reveal a new mechanism of receptor-mediated transactivation to modulate drug resistance, but also provide a novel drug target and direction for overcoming gefitinib resistance in NSCLC. Frontiers Media S.A. 2021-04-22 /pmc/articles/PMC8100583/ /pubmed/33967759 http://dx.doi.org/10.3389/fphar.2021.625289 Text en Copyright © 2021 Jiang, Zhuo, Fu, Wu and Mao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Jiang, Yuhong Zhuo, Xin Fu, Xiujuan Wu, Yue Mao, Canquan Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation |
title | Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation |
title_full | Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation |
title_fullStr | Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation |
title_full_unstemmed | Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation |
title_short | Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation |
title_sort | targeting par2 overcomes gefitinib resistance in non-small-cell lung cancer cells through inhibition of egfr transactivation |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100583/ https://www.ncbi.nlm.nih.gov/pubmed/33967759 http://dx.doi.org/10.3389/fphar.2021.625289 |
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