Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer

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.

Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB pathways, in lung adenocarcinoma cells

“…PGRMC1 contributes to acquired resistance to erlotinib. To elucidate the molecular mechanism of acquired EGFR-TKI resistance, we previously compared PC9 and PC9/ER cells by proteomics analysis 13 ; the results indicated that PGRMC1 expression in PC9/ER cells was 3.8-fold that in PC9 cells (Table 1). To validate the clinical relevance of PGRMC1, Kaplan-Meier plots regarding PGRMC1 expression and overall survival in the lung cancer revealed that high expression of PGRMC1 patients have less overall survival rate than low expression of PGRMC1 patients (Additional file 1: Fig.…”

“…By performing proteome analysis with a newly established erlotinib-resistant cell line, PC9/ER, derived from PC9 lung cancer cells 13 , we previously revealed progesterone membrane component 1 (PGRMC1) as a candidate protein involved in acquired resistance to erlotinib. Recently, PGRMC1 was reported to be overexpressed in breast cancer 14 , lung cancer 15 , and ovarian cancer 16 .…”

Identification of MMP1 as a potential gene conferring erlotinib resistance in non-small cell lung cancer based on bioinformatics analyses

“…Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an oral targeted anticancer drug for non-small cell lung cancer (NSCLC) treatment, and showing a significant improvement of survival in NSCLC [ 32 ]. However, erlotinib-acquired resistance is a tough obstacle to effectively treating NSCLC patients with EGFR mutant characteristics [ 33 – 35 ]. The mechanism underlying erlotinib resistance in NSCLC has not been fully investigated.…”

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

“…Hypoxic melanoma EVs carried a hypoxic signature consisting of six proteins (AKR7A2, DDX39B, EIF3C, FARSA, PRMT5, VARS) which were significantly associated with a poor prognosis for melanoma patients. EIF3C promotes proliferation, migration and invasion of prostate [46], ovarian and hepatocellular carcinoma cells [47,48] and was associated with resistance to erlotinib in lung cancer [49]. PRMT5 (Protein arginine methyltransferase 5) is upregulated under hypoxia [50] and has many roles in cancer [51].…”