Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer.
Identifieur interne : 000C37 ( Main/Exploration ); précédent : 000C36; suivant : 000C38Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer.
Auteurs : Takuya Shintani [Japon] ; Kazuma Higashisaka [Japon] ; Makiko Maeda [Japon] ; Masaya Hamada [Japon] ; Ryosuke Tsuji [Japon] ; Koudai Kurihara [Japon] ; Yuri Kashiwagi [Japon] ; Atsuhiro Sato [Japon] ; Masanori Obana [Japon] ; Ayaha Yamamoto [Japon] ; Keisuke Kawasaki [Japon] ; Ying Lin [Japon] ; Takashi Kijima [Japon] ; Yuhei Kinehara [Japon] ; Yoshihiro Miwa [Japon] ; Shinichiro Maeda [Japon] ; Eiichi Morii [Japon] ; Atsushi Kumanogoh [Japon] ; Yasuo Tsutsumi [Japon] ; Izumi Nagatomo [Japon] ; Yasushi Fujio [Japon]Source :
- Oncotarget [ 1949-2553 ] ; 2018.
Abstract
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.
DOI: 10.18632/oncotarget.26494
PubMed: 30680067
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Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Tsutsumi, Yasuo" sort="Tsutsumi, Yasuo" uniqKey="Tsutsumi Y" first="Yasuo" last="Tsutsumi">Yasuo Tsutsumi</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Nagatomo, Izumi" sort="Nagatomo, Izumi" uniqKey="Nagatomo I" first="Izumi" last="Nagatomo">Izumi Nagatomo</name><affiliation wicri:level="1"><nlm:affiliation>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Fujio, Yasushi" sort="Fujio, Yasushi" uniqKey="Fujio Y" first="Yasushi" last="Fujio">Yasushi Fujio</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:30680067</idno><idno type="pmid">30680067</idno><idno 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cancer.</title><author><name sortKey="Shintani, Takuya" sort="Shintani, Takuya" uniqKey="Shintani T" first="Takuya" last="Shintani">Takuya Shintani</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Higashisaka, Kazuma" sort="Higashisaka, Kazuma" uniqKey="Higashisaka K" first="Kazuma" last="Higashisaka">Kazuma Higashisaka</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Maeda, Makiko" sort="Maeda, Makiko" uniqKey="Maeda M" first="Makiko" last="Maeda">Makiko Maeda</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Hamada, Masaya" sort="Hamada, Masaya" uniqKey="Hamada M" first="Masaya" last="Hamada">Masaya Hamada</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Tsuji, Ryosuke" sort="Tsuji, Ryosuke" uniqKey="Tsuji R" first="Ryosuke" last="Tsuji">Ryosuke Tsuji</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Kurihara, Koudai" sort="Kurihara, Koudai" uniqKey="Kurihara K" first="Koudai" last="Kurihara">Koudai Kurihara</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Kashiwagi, Yuri" sort="Kashiwagi, Yuri" uniqKey="Kashiwagi Y" first="Yuri" last="Kashiwagi">Yuri Kashiwagi</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Sato, Atsuhiro" sort="Sato, Atsuhiro" uniqKey="Sato A" first="Atsuhiro" last="Sato">Atsuhiro Sato</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Obana, Masanori" sort="Obana, Masanori" uniqKey="Obana M" first="Masanori" last="Obana">Masanori Obana</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Yamamoto, Ayaha" sort="Yamamoto, Ayaha" uniqKey="Yamamoto A" first="Ayaha" last="Yamamoto">Ayaha Yamamoto</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Kawasaki, Keisuke" sort="Kawasaki, Keisuke" uniqKey="Kawasaki K" first="Keisuke" last="Kawasaki">Keisuke Kawasaki</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Osaka University Graduate School of Medicine, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pathology, Osaka University Graduate School of Medicine, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Lin, Ying" sort="Lin, Ying" uniqKey="Lin Y" first="Ying" last="Lin">Ying Lin</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Kijima, Takashi" sort="Kijima, Takashi" uniqKey="Kijima T" first="Takashi" last="Kijima">Takashi Kijima</name><affiliation wicri:level="1"><nlm:affiliation>Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya</wicri:regionArea><wicri:noRegion>Nishinomiya</wicri:noRegion></affiliation></author><author><name sortKey="Kinehara, Yuhei" sort="Kinehara, Yuhei" uniqKey="Kinehara Y" first="Yuhei" last="Kinehara">Yuhei Kinehara</name><affiliation wicri:level="1"><nlm:affiliation>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Miwa, Yoshihiro" sort="Miwa, Yoshihiro" uniqKey="Miwa Y" first="Yoshihiro" last="Miwa">Yoshihiro Miwa</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, Osaka University Hospital, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pharmacy, Osaka University Hospital, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Maeda, Shinichiro" sort="Maeda, Shinichiro" uniqKey="Maeda S" first="Shinichiro" last="Maeda">Shinichiro Maeda</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Morii, Eiichi" sort="Morii, Eiichi" uniqKey="Morii E" first="Eiichi" last="Morii">Eiichi Morii</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Osaka University Graduate School of Medicine, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pathology, Osaka University Graduate School of Medicine, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Kumanogoh, Atsushi" sort="Kumanogoh, Atsushi" uniqKey="Kumanogoh A" first="Atsushi" last="Kumanogoh">Atsushi Kumanogoh</name><affiliation wicri:level="1"><nlm:affiliation>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Tsutsumi, Yasuo" sort="Tsutsumi, Yasuo" uniqKey="Tsutsumi Y" first="Yasuo" last="Tsutsumi">Yasuo Tsutsumi</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Nagatomo, Izumi" sort="Nagatomo, Izumi" uniqKey="Nagatomo I" first="Izumi" last="Nagatomo">Izumi Nagatomo</name><affiliation wicri:level="1"><nlm:affiliation>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author><author><name sortKey="Fujio, Yasushi" sort="Fujio, Yasushi" uniqKey="Fujio Y" first="Yasushi" last="Fujio">Yasushi Fujio</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Graduate School of Pharmaceutical Sciences, Osaka University, Suita</wicri:regionArea><wicri:noRegion>Suita</wicri:noRegion></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Japon</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Shintani, Takuya" sort="Shintani, Takuya" uniqKey="Shintani T" first="Takuya" last="Shintani">Takuya Shintani</name></noRegion><name sortKey="Fujio, Yasushi" sort="Fujio, Yasushi" uniqKey="Fujio Y" first="Yasushi" last="Fujio">Yasushi Fujio</name><name sortKey="Hamada, Masaya" sort="Hamada, Masaya" uniqKey="Hamada M" first="Masaya" last="Hamada">Masaya Hamada</name><name sortKey="Higashisaka, Kazuma" sort="Higashisaka, Kazuma" uniqKey="Higashisaka K" first="Kazuma" last="Higashisaka">Kazuma Higashisaka</name><name sortKey="Kashiwagi, Yuri" sort="Kashiwagi, Yuri" uniqKey="Kashiwagi Y" first="Yuri" last="Kashiwagi">Yuri Kashiwagi</name><name sortKey="Kawasaki, Keisuke" sort="Kawasaki, Keisuke" uniqKey="Kawasaki K" first="Keisuke" last="Kawasaki">Keisuke Kawasaki</name><name sortKey="Kijima, Takashi" sort="Kijima, Takashi" uniqKey="Kijima T" first="Takashi" last="Kijima">Takashi Kijima</name><name sortKey="Kinehara, Yuhei" sort="Kinehara, Yuhei" uniqKey="Kinehara Y" first="Yuhei" last="Kinehara">Yuhei Kinehara</name><name sortKey="Kumanogoh, Atsushi" sort="Kumanogoh, Atsushi" uniqKey="Kumanogoh A" first="Atsushi" last="Kumanogoh">Atsushi Kumanogoh</name><name sortKey="Kurihara, Koudai" sort="Kurihara, Koudai" uniqKey="Kurihara K" first="Koudai" last="Kurihara">Koudai Kurihara</name><name sortKey="Lin, Ying" sort="Lin, Ying" uniqKey="Lin Y" first="Ying" last="Lin">Ying Lin</name><name sortKey="Maeda, Makiko" sort="Maeda, Makiko" uniqKey="Maeda M" first="Makiko" last="Maeda">Makiko Maeda</name><name sortKey="Maeda, Shinichiro" sort="Maeda, Shinichiro" uniqKey="Maeda S" first="Shinichiro" last="Maeda">Shinichiro Maeda</name><name sortKey="Miwa, Yoshihiro" sort="Miwa, Yoshihiro" uniqKey="Miwa Y" first="Yoshihiro" last="Miwa">Yoshihiro Miwa</name><name sortKey="Morii, Eiichi" sort="Morii, Eiichi" uniqKey="Morii E" first="Eiichi" last="Morii">Eiichi Morii</name><name sortKey="Nagatomo, Izumi" sort="Nagatomo, Izumi" uniqKey="Nagatomo I" first="Izumi" last="Nagatomo">Izumi Nagatomo</name><name sortKey="Obana, Masanori" sort="Obana, Masanori" uniqKey="Obana M" first="Masanori" last="Obana">Masanori Obana</name><name sortKey="Sato, Atsuhiro" sort="Sato, Atsuhiro" uniqKey="Sato A" first="Atsuhiro" last="Sato">Atsuhiro Sato</name><name sortKey="Tsuji, Ryosuke" sort="Tsuji, Ryosuke" uniqKey="Tsuji R" first="Ryosuke" last="Tsuji">Ryosuke Tsuji</name><name sortKey="Tsutsumi, Yasuo" sort="Tsutsumi, Yasuo" uniqKey="Tsutsumi Y" first="Yasuo" last="Tsutsumi">Yasuo Tsutsumi</name><name sortKey="Yamamoto, Ayaha" sort="Yamamoto, Ayaha" uniqKey="Yamamoto A" first="Ayaha" last="Yamamoto">Ayaha Yamamoto</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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