JNK/SAPK activity is not sufficient for anticancer therapy-induced apoptosis involving CD95-L, TRAIL and TNF-alpha

Int J Cancer. 1999 Jan 29;80(3):417-24. doi: 10.1002/(sici)1097-0215(19990129)80:3<417::aid-ijc14>3.0.co;2-b.

Abstract

We report here that stress stimuli such as gamma-irradiation or the anticancer drug doxorubicin activate expression of the death-inducing ligands (DILs) CD95-L, TNF-alpha and TRAIL. Apoptosis induced by gamma-irradiation or doxorubicin engages a FADD- and caspase-dependent apoptosis pathway which is inhibited by dominant negative FADD or the caspase inhibitor zVAD. zVAD did not prevent activity of JNK/SAPKs in response to doxorubicin suggesting that JNK/SAPK activity is independent of death receptor triggering during cellular stress-induced apoptosis. In addition, JNK/SAPKs remained activated by doxorubicin in resistant cell lines in which cleavage of caspases and apoptosis was not observed. These data uncouple JNK/SAPK activation and apoptosis signaling and indicate that cellular stress-induced apoptosis involves signaling via DILs which is paralleled by activation of JNK/SAPKs. Activation of these kinases may contribute e.g., to the expression of molecules involved in apoptosis but is not sufficient for induction of the apoptosis program following cellular stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Arabidopsis Proteins*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Caspases / metabolism
  • Doxorubicin / pharmacology
  • Enzyme Activation
  • Fatty Acid Desaturases / metabolism
  • Humans
  • Jurkat Cells / drug effects
  • Jurkat Cells / radiation effects
  • Membrane Glycoproteins / metabolism*
  • Mitogen-Activated Protein Kinases*
  • Neoplasm Proteins / metabolism*
  • Plant Proteins / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / radiation effects
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation
  • fas Receptor / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Arabidopsis Proteins
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Plant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Doxorubicin
  • Fatty Acid Desaturases
  • Fad7 protein, Arabidopsis
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Caspases