Abstract: The GCN2-eIF2α pathway regulates cell growth and serves as a key component of the integrated stress response (ISR). In malignant tumors, cancer cells reside in a microenvironment characterized by chronic hypoxia and nutrient deprivation. Under such conditions, the level of amino acid catabolism increases, which activates the GCN2-eIF2α pathway and inhibits protein synthesis to maintain the cellular homeostasis of cancer cells. In this study, a total of 9 pairs of tissue samples, including cancerous tissues and their matched adjacent normal tissues, were collected from patients diagnosed with non-small cell lung cancer (NSCLC). A combined analysis using histology, transcriptomics, qRT-PCR, and Western blotting was performed to investigate the molecular mechanism by which the GCN2-eIF2α pathway regulates cancer cell proliferation. Results of paraffin sections showed that in the tumor tissues of lung cancer patients, alveolar cells were densely packed, alveolar septa were narrow, and nuclear staining was heterogeneous, exhibiting typical malignant histopathological features. Transcriptomic studies revealed that the enriched pathways and differentially expressed genes among samples were identified based on gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment results from the transcriptome, which confirmed that the GCN2-eIF2α pathway plays an important role in lung carcinogenesis. Further screening was performed to select key genes for validation at the molecular and protein levels. qRT-PCR results demonstrated that these genes were expressed in both cancerous and normal tissue cells, with their expression levels mostly upregulated in cancerous tissue cells (P<0.05), which was consistent with the gene abundance analysis results in the transcriptome. At the protein level, the expression levels of general control nonderepressible 2 kinase (GCN2) and eukaryotic translation initiation 2α (eIF2α) in cancerous tissues were significantly higher than those in adjacent normal tissues, indicating that the GCN2-eIF2α pathway is implicated in lung carcinogenesis. This study can provide a reference for eIF2α and GCN2 to serve as new therapeutic targets for tumors, and also propose the possibility of inhibiting cancer cell progression by suppressing GCN2-mediated phosphorylation of eIF2α, thereby offering a solution to address the limitations of current anti-tumor therapies.
Key words: lung cancer; GCN2-eIF2α pathway; transcriptomics; cancer pathogenesis; targeted tumor therapy
（Acta Laser Biology Sinica, 2025, 34(6): 530-540）