To identify novel therapeutic targets for non-small cell lung cancer (NSCLC), we conducted an integrative study in the following 3 stages: (i) identification of potential target gene(s) through shRNA functional screens in 2 independent NSCLC cell lines; (ii) validation of the clinical relevance of identified gene(s) using public databases; and (iii) investigation of therapeutic potential of targeting the identified gene(s) in vitro. A semi-genome-wide shRNA screen was performed in NCI-H358 cells, and was integrated with data from our previous screen in NCI-H460 cells. Among genes identified in shRNA screens, 24 were present in both NCI-H358 and NCI-H460 cells and were considered potential targets. Among the genes, we focused on eIF2β, which is a subunit of heterotrimeric G protein EIF2 and functions as a transcription initiation factor. The eIF2β protein is highly expressed in lung cancer cell lines compared with normal bronchial epithelial cells, and gene copy number analyses revealed that eIF2β is amplified in a subset of NSCLC cell lines. Gene expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that eIF2β expression is significantly upregulated in lung cancer tissues compared with corresponding normal lung tissues. Furthermore, high eIF2β expression was correlated with poor survival in patients with lung adenocarcinoma, as shown in other cohorts using publicly available online tools. RNAi-mediated depletion of eIF2β suppresses growth of lung cancer cells independently of p53 mutation status, in part through G1 cell cycle arrest. Our data suggest that eIF2β is a therapeutic target for lung cancer.
Keywords: G1 phase cell cycle checkpoints; RNA interference; adenocarcinoma; eukaryotic initiation factor-2; heterotrimeric GTP-binding proteins.
© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.