The correlation of p22 ^phox and chemosensitivity in EGFR-TKI resistant lung adenocarcinoma

Background: Enhancing the chemosensitivity in the patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistant lung adenocarcinoma (LUAD) is pivotal in achieving their successful therapeutic outcome. We aimed to explore the mechanisms regarding the development of therapeutic resistance to chemotherapy in EGFR-TKI resistant LUAD. Methods: Microarray analysis lead to potential involvement of p22 ^phox , which was abundantly expressed in the cell lines harboring EGFR-TKI resistance and chemoresistance, and was known to regulate several important chemoresistance-associated factors such as hypoxia inducible factor-1α (HIF-1α) and epithelial-mesenchymal transition (EMT). We compared the status of p22 ^phox with that of chemoresistance, HIF-1α expression and EMT in LUAD cell lines. We immunolocalized p22 ^phox in the specimens of lung cancer patients. Results: p22 ^phox and HIF-1α mRNAs were significantly elevated in the cells harboring EMT and chemoresistance. p22 ^phox knockdown enhanced chemosensitivity and reduced the expression of HIF-1α and EMT-associated factors. HIF-1α knockdown enhanced the chemosensitivity, while HIF-1α transfection induced EMT and chemoresistance in these cell lines. All LUAD patients with T790M mutation were associated with abundant p22 ^phox immunoreactivity in carcinoma cells. Conclusions: The analysis of p22 ^phox in lung carcinoma tissues could provide new insights into the selection of chemotherapy for the patients with EGFR-TKI resistant LUAD.