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

ABSTRACT:

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-1? (HIF-1?) and epithelial-mesenchymal transition (EMT). We compared the status of p22^phox with that of chemoresistance, HIF-1? expression and EMT in LUAD cell lines. We immunolocalized p22^phox in the specimens of lung cancer patients.

Results

p22^phox and HIF-1? mRNAs were significantly elevated in the cells harboring EMT and chemoresistance. p22^phox knockdown enhanced chemosensitivity and reduced the expression of HIF-1? and EMT-associated factors. HIF-1? knockdown enhanced the chemosensitivity, while HIF-1? 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.

SUBMITTER: Kobayashi M

PROVIDER: S-EPMC6383684 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

The correlation of p22<sup>phox</sup> and chemosensitivity in EGFR-TKI resistant lung adenocarcinoma.

Kobayashi Masayuki M Saito Ryoko R Miki Yasuhiro Y Nanamiya Ren R Inoue Chihiro C Abe Jiro J Sato Ikuro I Okada Yoshinori Y Sasano Hironobu H

Oncotarget 20190201 10

<h4>Background</h4>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<sup>phox</sup>, which was abundantly expressed in the cell line ...[more]

PMID: 30800222

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Project description:BACKGROUND:The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer. METHODS:We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples. RESULTS:Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma. CONCLUSION:Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.