4-Hydroxynonenal triggers an epidermal growth factor receptor-linked signal pathway for growth inhibition

Wei Liu, Anwarul A. Akhand, Masashi Kato, Itsuo Yokoyama, Toshio Miyata, Kiyoshi Kurokawa, Koji Uchida, Izumi Nakashima

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136 Citations (Scopus)

Abstract

Lipid peroxidation has been implicated in the pathogenesis of various diseases. As a major product of membrane lipid peroxidation, 4-hydroxynonenal (HNE) appears after various kinds of oxidative stress, and is known to induce cell growth inhibition. We here analysed the HNE-mediated signal transduction cascade for the growth inhibition of human epidermoid carcinoma A431 cells. HNE dose-dependently induced phosphorylation of multiple cellular proteins including epidermal growth factor receptor (EGFR) in A431 cells, and rapidly upregulated the catalytic actions of EGFR for autophosphorylation and for phosphorylation of casein as an exogenous substrate. Immunoblot analysis by use of HNE-specific antibody demonstrated the binding of HNE to EGFR along with its activation. This binding, which did not induce cross-linking of EGFR, caused a capping of the receptor on the cell surface which mimicked the capping induced by EGF. Phosphorylation and activation of EGFR were followed by phosphorylation of adaptor protein Shc and activation of MAP kinase. Both genistein as a wide spectrum protein tyrosine kinase inhibitor and AG1478 as a specific EGFR tyrosine phosphorylation blocker inhibited activation of EGFR and MAP kinase by HNE. The same inhibitors prevented HNE-mediated growth inhibition, suggesting a close linkage between EGFR/MAP kinase activation and growth inhibition after exposure to HNE. Our results suggest that EGFR may be one of the primary targets of HNE for an oxidative stress-linked cell growth inhibition.

Original languageEnglish
Pages (from-to)2409-2417
Number of pages9
JournalJournal of cell science
Volume112
Issue number14
Publication statusPublished - 1999 Aug 23
Externally publishedYes

Keywords

  • 4-Hydroxynonenal
  • EGFR
  • Growth inhibition
  • MAPK
  • Receptor clustering

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Liu, W., Akhand, A. A., Kato, M., Yokoyama, I., Miyata, T., Kurokawa, K., Uchida, K., & Nakashima, I. (1999). 4-Hydroxynonenal triggers an epidermal growth factor receptor-linked signal pathway for growth inhibition. Journal of cell science, 112(14), 2409-2417.