CD44 variant–dependent regulation of redox balance in EGFR mutation–positive non–small cell lung cancer: A target for treatment. (November 2017)

• Record Type: Journal Article
• Authors: Kawano, Yuko; Iwama, Eiji; Tsuchihashi, Kenji; Shibahara, Daisuke; Harada, Taishi; Tanaka, Kentaro; Nagano, Osamu; Saya, Hideyuki; Nakanishi, Yoichi; Okamoto, Isamu
• Is Part Of: Lung cancer. Volume 113(2017)
• Page Start: 72
• Page End: 78
• Publication Date: 2017-11
• Subjects: CD44 variant (CD44v) -- Reactive oxygen species (ROS) -- Epidermal growth factor receptor (EGFR) -- Non–small cell lung cancer (NSCLC) -- Glutathione -- Chemosensitization; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2017.09.008
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: EGFR signaling induced by EGFR mutation increases intracellular ROS levels. CD44v is overexpressed in EGFR -mutated NSCLC cells with low basal ROS levels. CD44v regulates redox balance through glutathione in EGFR -mutated NSCLC cells. CD44v depletion enhances cisplatin cytotoxicity in CD44v high EGFR -mutated NSCLC cells. Abstract: Objectives: The regulation of redox balance in cancer cells is an important factor in tumor development and chemoresistance, with oncogene activation having been shown to induce the generation of reactive oxygen species (ROS). Activating mutations of the epidermal growth factor receptor gene ( EGFR ) are oncogenic drivers in non–small cell lung cancer (NSCLC), but it has remained unknown whether ligand-independent EGFR signaling conferred by EGFR mutation triggers ROS generation in NSCLC cells. Materials and Methods: HEK293T cells were transfected with an expression vector for mutant EGFR. The expression of CD44 variant (CD44v) isoforms in NSCLC cell lines was evaluated by flow cytometry. Cells were depleted of CD44v by RNA interference and assayed for ROS and glutathione (GSH) levels. The effect of CD44v on cisplatin sensitivity was evaluated in vitro with the MTS assay. Results: EGFR signaling due to EGFR mutation increased ROS levels in transfected HEK293T cells. The expression of CD44v isoforms was found to be inversely correlated with basal ROS levels in EGFR mutation–positive NSCLC cell lines. Knockdown of CD44v induced depletion of intracellular GSH and increased ROS levels in EGFR- mutated NSCLC cells that express CD44v at a high level (CD44v high ). In addition, depletion of GSH by treatment with buthionine-[ S, R ]-sulfoximine induced marked accumulation of ROS and enhanced the cytotoxicity of cisplatin in CD44v high EGFR- mutated NSCLC cells but not in corresponding CD44v low cells. This enhancement of cisplatin cytotoxicity by GSH depletion was prevented by treatment with the antioxidant N -acetyl-l -cysteine. Knockdown of CD44v also enhanced cisplatin cytotoxicity in CD44v high EGFR mutation–positive NSCLC cells but not in CD44v low cells. Conclusion: Our results thus implicate CD44v in redox adaptation and as a potential target for treatment in CD44v high EGFR- mutated NSCLC cells.