Abstract
Lung cancers are frequently characterized by inappropriate activation of epidermal growth factor receptor (EGFR)-dependent signaling and epigenetic silencing of the NADPH oxidase (NOX) enzyme DUOX1, both potentially contributing to worse prognosis. Based on previous findings linking DUOX1 with redox-dependent EGFR activation, the present studies were designed to evaluate whether DUOX1 silencing in lung cancers may be responsible for altered EGFR regulation. In contrast to normal epithelial cells, EGF stimulation of lung cancer cell lines that lack DUOX1 promotes EGF-induced EGFR internalization and nuclear localization, associated with induction of EGFR-regulated genes and related tumorigenic outcomes. Each of these outcomes could be reversed by overexpression of DUOX1 or enhanced by shRNA-dependent DUOX1 silencing. EGF-induced nuclear EGFR localization in DUOX1-deficient lung cancer cells was associated with altered dynamics of cysteine oxidation of EGFR, and an overall reduction of EGFR cysteines. These various outcomes could also be attenuated by silencing of glutathione S-transferase P1 (GSTP1), a mediator of metabolic alterations and drug resistance in various cancers, and a regulator of cysteine oxidation. Collectively, our findings indicate DUOX1 deficiency in lung cancers promotes dysregulated EGFR signaling and enhanced GSTP1-mediated turnover of EGFR cysteine oxidation, which result in enhanced nuclear EGFR localization and tumorigenic properties.
Highlights
Lung cancer remains to be the leading cause of cancer-related mortality, claiming roughly 1.6 million lives annually worldwide and nearly 150,000 alone in the United States[1,2]
Based on previous studies indicating DUOX1 silencing in lung cancers and its impact on resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors[9], we evaluated basal activity and subcellular localization of EGFR within various lung cancer cell lines in relation to DUOX1 expression
We present evidence that the extent of Nuclear EGFR (nEGFR) localization in lung cancer cells is determined by the presence or absence of DUOX1, an NADPH oxidase homolog that is important for normal epithelial function and is closely associated with regulating EGFR-dependent innate responses to infection or injury[28,35]
Summary
Lung cancer remains to be the leading cause of cancer-related mortality, claiming roughly 1.6 million lives annually worldwide and nearly 150,000 alone in the United States[1,2]. Dysregulated EGFR signaling is a well-appreciated component of most epithelial cancers, which is manifested by increased expression and activation of this kinase In some cases, this is related to EGFR-activating mutations (e.g. L858R, exon 19 del, etc.), which has fueled the design of molecular-based therapeutics, such as EGFR tyrosine kinase inhibitors, this has been complicated by the development of acquired resistance due to secondary EGFR mutations or alternative resistance mechanisms[10,11,12], and has resulted in development of generation EGFR-targeted therapies[13,14,15]. Conversion to R-SOH) can enhance kinase function, and that subsequent conjugation with GSH (to form S-glutathionylated EGFR; R-SSG) is likely responsible for restoring inactive EGFR and preventing further irreversible oxidation[26,27] Such EGFR sulfenylation is mediated by activation of NOX isoforms including DUOX1, especially in the context of innate epithelial responses to common airborne triggers[27,28]. We demonstrate that such turnover of cysteine oxidation and nEGFR function depends on the presence of glutathione S-transferase P 1 (GSTP1), a known catalyst of GSH conjugation to oxidized cysteines and an important determinant of metabolic dysfunction and pathogenicity in cancer
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