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Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer
The acquisition of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is one of the major problems in the pharmacotherapy against non-small cell lung cancers; however, molecular mechanisms remain to be fully elucidated. Here, using a newly-established erlotinib-resistant cell line, PC9/ER, fr...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331022/ https://www.ncbi.nlm.nih.gov/pubmed/30680067 http://dx.doi.org/10.18632/oncotarget.26494 |
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author | Shintani, Takuya Higashisaka, Kazuma Maeda, Makiko Hamada, Masaya Tsuji, Ryosuke Kurihara, Koudai Kashiwagi, Yuri Sato, Atsuhiro Obana, Masanori Yamamoto, Ayaha Kawasaki, Keisuke Lin, Ying Kijima, Takashi Kinehara, Yuhei Miwa, Yoshihiro Maeda, Shinichiro Morii, Eiichi Kumanogoh, Atsushi Tsutsumi, Yasuo Nagatomo, Izumi Fujio, Yasushi |
author_facet | Shintani, Takuya Higashisaka, Kazuma Maeda, Makiko Hamada, Masaya Tsuji, Ryosuke Kurihara, Koudai Kashiwagi, Yuri Sato, Atsuhiro Obana, Masanori Yamamoto, Ayaha Kawasaki, Keisuke Lin, Ying Kijima, Takashi Kinehara, Yuhei Miwa, Yoshihiro Maeda, Shinichiro Morii, Eiichi Kumanogoh, Atsushi Tsutsumi, Yasuo Nagatomo, Izumi Fujio, Yasushi |
author_sort | Shintani, Takuya |
collection | PubMed |
description | The acquisition of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is one of the major problems in the pharmacotherapy against non-small cell lung cancers; however, molecular mechanisms remain to be fully elucidated. Here, using a newly-established erlotinib-resistant cell line, PC9/ER, from PC9 lung cancer cells, we demonstrated that the expression of translation-related molecules, including eukaryotic translation initiation factor 3 subunit C (eIF3c), was upregulated in PC9/ER cells by proteome analyses. Immunoblot analyses confirmed that eIF3c protein increased in PC9/ER cells, compared with PC9 cells. Importantly, the knockdown of eIF3c with its siRNAs enhanced the drug sensitivity in PC9/ER cells. Mechanistically, we found that LC3B-II was upregulated in PC9/ER cells, while downregulated by the knockdown of eIF3c. Consistently, the overexpression of eIF3c increased the number of autophagosomes, proposing the causality between eIF3c expression and autophagy. Moreover, chloroquine, an autophagy inhibitor, restored the sensitivity to erlotinib. Finally, immunohistochemical analyses of biopsy samples showed that the frequency of eIF3c-positive cases was higher in the patients with EGFR-TKI resistance than those prior to EGFR-TKI treatment. Moreover, the eIF3c-positive cases exhibited poor prognosis in EGFR-TKI treatment. Collectively, the upregulation of eIF3c could impair the sensitivity to EGFR-TKI as a novel mechanism of the drug resistance. |
format | Online Article Text |
id | pubmed-6331022 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-63310222019-01-24 Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer Shintani, Takuya Higashisaka, Kazuma Maeda, Makiko Hamada, Masaya Tsuji, Ryosuke Kurihara, Koudai Kashiwagi, Yuri Sato, Atsuhiro Obana, Masanori Yamamoto, Ayaha Kawasaki, Keisuke Lin, Ying Kijima, Takashi Kinehara, Yuhei Miwa, Yoshihiro Maeda, Shinichiro Morii, Eiichi Kumanogoh, Atsushi Tsutsumi, Yasuo Nagatomo, Izumi Fujio, Yasushi Oncotarget Research Paper The acquisition of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is one of the major problems in the pharmacotherapy against non-small cell lung cancers; however, molecular mechanisms remain to be fully elucidated. Here, using a newly-established erlotinib-resistant cell line, PC9/ER, from PC9 lung cancer cells, we demonstrated that the expression of translation-related molecules, including eukaryotic translation initiation factor 3 subunit C (eIF3c), was upregulated in PC9/ER cells by proteome analyses. Immunoblot analyses confirmed that eIF3c protein increased in PC9/ER cells, compared with PC9 cells. Importantly, the knockdown of eIF3c with its siRNAs enhanced the drug sensitivity in PC9/ER cells. Mechanistically, we found that LC3B-II was upregulated in PC9/ER cells, while downregulated by the knockdown of eIF3c. Consistently, the overexpression of eIF3c increased the number of autophagosomes, proposing the causality between eIF3c expression and autophagy. Moreover, chloroquine, an autophagy inhibitor, restored the sensitivity to erlotinib. Finally, immunohistochemical analyses of biopsy samples showed that the frequency of eIF3c-positive cases was higher in the patients with EGFR-TKI resistance than those prior to EGFR-TKI treatment. Moreover, the eIF3c-positive cases exhibited poor prognosis in EGFR-TKI treatment. Collectively, the upregulation of eIF3c could impair the sensitivity to EGFR-TKI as a novel mechanism of the drug resistance. Impact Journals LLC 2018-12-25 /pmc/articles/PMC6331022/ /pubmed/30680067 http://dx.doi.org/10.18632/oncotarget.26494 Text en Copyright: © 2018 Shintani et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Shintani, Takuya Higashisaka, Kazuma Maeda, Makiko Hamada, Masaya Tsuji, Ryosuke Kurihara, Koudai Kashiwagi, Yuri Sato, Atsuhiro Obana, Masanori Yamamoto, Ayaha Kawasaki, Keisuke Lin, Ying Kijima, Takashi Kinehara, Yuhei Miwa, Yoshihiro Maeda, Shinichiro Morii, Eiichi Kumanogoh, Atsushi Tsutsumi, Yasuo Nagatomo, Izumi Fujio, Yasushi Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer |
title | Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer |
title_full | Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer |
title_fullStr | Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer |
title_full_unstemmed | Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer |
title_short | Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer |
title_sort | eukaryotic translation initiation factor 3 subunit c is associated with acquired resistance to erlotinib in non-small cell lung cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331022/ https://www.ncbi.nlm.nih.gov/pubmed/30680067 http://dx.doi.org/10.18632/oncotarget.26494 |
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