N-acetyl-l-cysteine fosters inactivation and transfer to endolysosomes of c-Src

Free Radic Biol Med. 2008 Dec 1;45(11):1566-72. doi: 10.1016/j.freeradbiomed.2008.09.012. Epub 2008 Sep 23.

Abstract

The non-receptor-protein tyrosine kinase c-Src is overexpressed and activated in a large number of human cancers, in which it is associated with tumor development and progression. Canonical regulation takes place by means of an alternative phosphorylation of tyrosine residues -- Tyr419 for activation and Tyr530 for inactivation. An independent redox regulation mechanism, involving cysteine residues, has also been proposed, in which oxidation activates the enzyme. Here we present a kinetic analysis of the effect of N-acetyl-l-cysteine (NAC) on c-Src, demonstrating that reduction reverts the oxidation-driven activation. In cancer cells, we show that NAC treatment produces an increase in specifically labeled reduced thiols of c-Src cysteines, thus confirming a redox transition. In addition to a decrease in Tyr419 phosphorylation, this leads to a massive shift of c-Src from plasma membranes -- where its active form is located -- to endolysosomal compartments. With the objective of deciphering the complex issue of c-Src regulation and of devising new strategies to revert its activation in cancers, redox regulation thus emerges as a promising area for study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / chemistry*
  • Acetylcysteine / pharmacology*
  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • CSK Tyrosine-Protein Kinase
  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Fluorescent Antibody Technique
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / pharmacology
  • Humans
  • Immunoprecipitation
  • Kinetics
  • Lysosomes / drug effects
  • Lysosomes / metabolism*
  • Microscopy, Confocal
  • Oxidation-Reduction / drug effects
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / isolation & purification
  • Protein-Tyrosine Kinases / metabolism*
  • Rats
  • src-Family Kinases

Substances

  • Free Radical Scavengers
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • Acetylcysteine