Identification of SNF1/AMP kinase-related kinase as an NF-kappaB-regulated anti-apoptotic kinase involved in CD95-induced motility and invasiveness

J Biol Chem. 2004 Nov 5;279(45):46742-7. doi: 10.1074/jbc.M404334200. Epub 2004 Sep 3.

Abstract

The death receptor CD95 (APO-1/Fas) induces apoptosis in many tissues. However, in apoptosis-resistant tumor cells, stimulation of CD95 induces up-regulation of a defined number of mostly anti-apoptotic genes, resulting in increased motility and invasiveness of tumor cells. The majority of these genes are known NF-kappaB target genes. We have identified one of the CD95-regulated genes as the serine/threonine kinase (SNF1/AMP kinase-related kinase (SNARK)), which is induced in response to various forms of metabolic stress. We demonstrate that up-regulation of SNARK in response to CD95 ligand and tumor necrosis factor alpha depends on activation of NF-kappaB. Overexpression of SNARK rendered tumor cells more resistant, whereas a kinase-inactive mutant of SNARK sensitized cells to CD95-mediated apoptosis. Furthermore, small interfering RNA-mediated knockdown of SNARK increased the sensitivity of tumor cells to CD95 ligand- and TRAIL-induced apoptosis. Importantly, cells with reduced expression of SNARK also showed reduced motility and invasiveness in response to CD95 engagement. SNARK therefore represents an NF-kappaB-regulated anti-apoptotic gene that contributes to the tumor-promoting activity of CD95 in apoptosis-resistant tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Cell Death
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Glutathione Transferase / metabolism
  • HeLa Cells
  • Humans
  • Mutagenesis, Site-Directed
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Serine-Threonine Kinases / physiology*
  • RNA, Small Interfering / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation
  • fas Receptor / biosynthesis*

Substances

  • NF-kappa B
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Glutathione Transferase
  • NUAK2 protein, human
  • Protein Serine-Threonine Kinases