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The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer
The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non–small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806107/ https://www.ncbi.nlm.nih.gov/pubmed/29318780 http://dx.doi.org/10.1002/cam4.1282 |
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author | Nakanishi, Takao Menju, Toshi Nishikawa, Shigeto Takahashi, Koji Miyata, Ryo Shikuma, Kei Sowa, Terumasa Imamura, Naoto Hamaji, Masatsugu Motoyama, Hideki Hijiya, Kyoko Aoyama, Akihiro Sato, Toshihiko Chen‐Yoshikawa, Toyofumi F. Sonobe, Makoto Date, Hiroshi |
author_facet | Nakanishi, Takao Menju, Toshi Nishikawa, Shigeto Takahashi, Koji Miyata, Ryo Shikuma, Kei Sowa, Terumasa Imamura, Naoto Hamaji, Masatsugu Motoyama, Hideki Hijiya, Kyoko Aoyama, Akihiro Sato, Toshihiko Chen‐Yoshikawa, Toyofumi F. Sonobe, Makoto Date, Hiroshi |
author_sort | Nakanishi, Takao |
collection | PubMed |
description | The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non–small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB‐resistant (VR) lung cancer cells (NCI‐H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP‐binding Cassette Sub‐family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB‐resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies. |
format | Online Article Text |
id | pubmed-5806107 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-58061072018-02-16 The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer Nakanishi, Takao Menju, Toshi Nishikawa, Shigeto Takahashi, Koji Miyata, Ryo Shikuma, Kei Sowa, Terumasa Imamura, Naoto Hamaji, Masatsugu Motoyama, Hideki Hijiya, Kyoko Aoyama, Akihiro Sato, Toshihiko Chen‐Yoshikawa, Toyofumi F. Sonobe, Makoto Date, Hiroshi Cancer Med Cancer Biology The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non–small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB‐resistant (VR) lung cancer cells (NCI‐H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP‐binding Cassette Sub‐family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB‐resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies. John Wiley and Sons Inc. 2018-01-10 /pmc/articles/PMC5806107/ /pubmed/29318780 http://dx.doi.org/10.1002/cam4.1282 Text en © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Cancer Biology Nakanishi, Takao Menju, Toshi Nishikawa, Shigeto Takahashi, Koji Miyata, Ryo Shikuma, Kei Sowa, Terumasa Imamura, Naoto Hamaji, Masatsugu Motoyama, Hideki Hijiya, Kyoko Aoyama, Akihiro Sato, Toshihiko Chen‐Yoshikawa, Toyofumi F. Sonobe, Makoto Date, Hiroshi The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer |
title | The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer |
title_full | The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer |
title_fullStr | The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer |
title_full_unstemmed | The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer |
title_short | The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer |
title_sort | synergistic role of atp‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806107/ https://www.ncbi.nlm.nih.gov/pubmed/29318780 http://dx.doi.org/10.1002/cam4.1282 |
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