Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer
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Takuya Shintani1,2, Kazuma Higashisaka1,3, Makiko Maeda1, Masaya Hamada1, Ryosuke Tsuji1, Koudai Kurihara1, Yuri Kashiwagi1, Atsuhiro Sato1, Masanori Obana1, Ayaha Yamamoto1, Keisuke Kawasaki4, Ying Lin1, Takashi Kijima5,6, Yuhei Kinehara6, Yoshihiro Miwa2, Shinichiro Maeda1,2, Eiichi Morii4, Atsushi Kumanogoh6,7, Yasuo Tsutsumi1,8, Izumi Nagatomo6 and Yasushi Fujio1,7
1Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
2Department of Pharmacy, Osaka University Hospital, Suita, Japan
3Department of Legal Medicine, Osaka University Graduate School of Medicine, Suita, Japan
4Department of Pathology, Osaka University Graduate School of Medicine, Suita, Japan
5Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
6Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan
7Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan
8The Center for Advanced Medical Engineering and Informatics, Osaka University, Suita, Japan
Yasushi Fujio, email: firstname.lastname@example.org
Keywords: eukaryotic translation initiation factor 3 subunit C (eIF3c); non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); EGFR-TKI resistance; autophagy
Received: August 29, 2018 Accepted: December 10, 2018 Published: December 25, 2018
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.
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