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NADPH oxidase-produced superoxide mediates EGFR transactivation by c-Src in arsenic trioxide-stimulated human

Hong-Yu Tseng1, Zi-Miao Liu, Huei-Sheng Huang

  • 1Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Archives of Toxicology
|April 26, 2012
PubMed

Insights

Arsenic trioxide (ATO) induces reactive oxygen species (ROS) production in keratinocytes primarily via NADPH oxidase activation, regulated by c-Src. This pathway mediates ATO-induced cell arrest and apoptosis.

Area of Science:

  • Cell Biology
  • Toxicology
  • Oncology

Background:

  • Arsenic trioxide (ATO) is a known carcinogen but also used therapeutically for cancers and other ailments.
  • Previous research linked ATO-induced keratinocyte cytotoxicity to p21 expression, the c-Src/EGFR/ERK pathway, and reactive oxygen species (ROS) generation.

Purpose of the Study:

  • To elucidate the specific mechanisms of ATO-induced ROS production and its role in keratinocyte apoptosis.
  • To investigate the involvement of NADPH oxidase and its regulation by c-Src and EGFR signaling.

Main Methods:

  • Utilized confocal microscopy and flow cytometry to assess ROS production and cellular responses.
  • Employed specific inhibitors (apocynin, DPI, tiron, PP1, PD153035) and gene knockdown (p67(phox)) to dissect signaling pathways.
  • Analyzed protein phosphorylation (EGFR-Y845, EGFR-Y1173, ERK) and expression (p67(phox), p21).

Main Results:

  • ATO induced ROS production, dependent on NADPH oxidase activity and p67(phox) expression/translocation.
  • ATO treatment led to EGFR phosphorylation at Y845 and Y1173.
  • c-Src activation, not EGFR, was crucial for ATO-induced NADPH oxidase activation and subsequent ROS generation.
  • c-Src activation and ATO treatment stimulated EGFR-Y845/ERK phosphorylation, p21 expression, and keratinocyte arrest/apoptosis, which were mitigated by ROS scavengers or p67(phox) knockdown.

Conclusions:

  • NADPH oxidase is a primary source of ATO-induced ROS in keratinocytes.
  • c-Src signaling plays a key regulatory role in ATO-induced NADPH oxidase activation and downstream cellular effects.
  • The c-Src/NADPH oxidase pathway is critical for ATO-induced keratinocyte apoptosis.

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