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Published on: February 18, 2015
Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small
Takuya Shintani1,2, Kazuma Higashisaka1,3, Makiko Maeda1
1Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
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.
Insights
Upregulation of eukaryotic translation initiation factor 3 subunit C (eIF3c) drives resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer. Inhibiting eIF3c restores drug sensitivity by modulating autophagy.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is a significant challenge in non-small cell lung cancer (NSCLC) treatment.
- The precise molecular mechanisms underlying this resistance are not fully understood.
Purpose of the Study:
- To investigate the role of translation-related molecules in EGFR-TKI resistance.
- To elucidate the molecular mechanisms by which resistance develops and identify potential therapeutic targets.
Main Methods:
- Establishment of an erlotinib-resistant NSCLC cell line (PC9/ER).
- Proteome and immunoblot analyses to identify differentially expressed proteins.
- siRNA-mediated knockdown of eIF3c and assessment of drug sensitivity.
- Autophagy analysis, including autophagosome quantification and the use of autophagy inhibitors (chloroquine).
- Immunohistochemical analysis of patient biopsy samples.
Main Results:
- Eukaryotic translation initiation factor 3 subunit C (eIF3c) expression was significantly upregulated in erlotinib-resistant PC9/ER cells.
- Knockdown of eIF3c enhanced sensitivity to erlotinib and reduced LC3B-II levels, indicating a role in autophagy regulation.
- Overexpression of eIF3c increased autophagosome formation, suggesting a causal link between eIF3c and autophagy.
- Autophagy inhibition with chloroquine restored erlotinib sensitivity in resistant cells.
- Higher eIF3c expression correlated with EGFR-TKI resistance and poor prognosis in NSCLC patients.
Conclusions:
- Upregulation of eIF3c is a novel mechanism contributing to EGFR-TKI resistance in NSCLC.
- eIF3c modulates autophagy, and targeting this pathway can overcome drug resistance.
- eIF3c may serve as a predictive biomarker for EGFR-TKI treatment response and a therapeutic target.
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