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Dysregulated Redox Regulation Contributes to Nuclear EGFR Localization and Pathogenicity in Lung Cancer

Andrew C Little1,2, Milena Hristova1, Loes van Lith1

  • 1Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, 05405, USA.

Scientific Reports
|March 21, 2019
PubMed

Insights

DUOX1 deficiency in lung cancer promotes epidermal growth factor receptor (EGFR) signaling, leading to nuclear localization and increased tumorigenic properties. Restoring DUOX1 or inhibiting GSTP1 can reverse these effects, offering potential therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Lung cancers often exhibit aberrant epidermal growth factor receptor (EGFR) signaling and reduced expression of the NADPH oxidase (NOX) enzyme DUOX1.
  • DUOX1 is implicated in redox-dependent EGFR regulation, suggesting a link between DUOX1 silencing and altered EGFR activity in cancer.

Purpose of the Study:

  • To investigate whether DUOX1 silencing contributes to the dysregulated EGFR signaling observed in lung cancers.
  • To explore the mechanisms by which DUOX1 deficiency impacts EGFR regulation and promotes tumorigenic outcomes.

Main Methods:

  • Utilized lung cancer cell lines with varying DUOX1 expression levels (silenced or overexpressed).
  • Stimulated cells with epidermal growth factor (EGF) and assessed EGFR internalization, nuclear localization, and gene expression.
  • Analyzed EGFR cysteine oxidation dynamics and the role of glutathione S-transferase P1 (GSTP1).

Main Results:

  • EGF stimulation in DUOX1-deficient lung cancer cells led to increased EGFR internalization and nuclear localization, unlike in normal cells.
  • These changes were associated with the induction of EGFR-regulated genes and enhanced tumorigenic properties.
  • DUOX1 overexpression reversed these effects, while DUOX1 silencing exacerbated them.
  • EGFR nuclear localization was linked to altered cysteine oxidation of EGFR, which was modulated by GSTP1.

Conclusions:

  • DUOX1 deficiency in lung cancer promotes dysregulated EGFR signaling, characterized by enhanced nuclear EGFR localization.
  • This process involves altered EGFR cysteine oxidation, partly mediated by GSTP1.
  • Restoring DUOX1 or inhibiting GSTP1 may represent therapeutic avenues for lung cancer by normalizing EGFR signaling.

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