Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-CBL-dependent MAPK/ERK pathway

Cancer Biol Ther. 2011 Sep 15;12(6):494-502. doi: 10.4161/cbt.12.6.15973. Epub 2011 Sep 15.


Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family that induces apoptosis in cancer cells. However, gastric cancer cells are insensitive to TRAIL. In the present study, we show that pretreatment with IFN-α enhanced TRAIL-induced apoptosis of gastric cancer MGC803 cells. IFN-α up-regulated death receptor 5 (DR5) expression and down-regulated survivin expression. Furthermore, extracellular-regulated protein kinase (ERK1/2) activation was induced by IFN-α, and a combination of IFN-α and TRAIL led to further activation of ERK1/2. Inhibition of the MAPK/ERK signaling pathway partially reversed apoptosis, as well as the expression patterns of DR5 and survivin. Moreover, the expression of the c-casitas B-lineage lymphoma (c-Cbl) family was down-regulated by IFN-α. Transfection of c-Cbl suppressed IFN-α-induced ERK activation. These results indicate that IFN-α enhances TRAIL-induced apoptosis in gastric cancer cells at least partially via downregulation of c-Cbl, and subsequent up-regulation of the MAPK/ERK pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Caspases / metabolism
  • Cell Line, Tumor
  • Drug Synergism
  • Enzyme Activation
  • Gene Expression
  • Humans
  • Interferon-alpha / pharmacology*
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Stomach Neoplasms
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Interferon-alpha
  • Protein Kinase Inhibitors
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Proto-Oncogene Proteins c-cbl
  • Mitogen-Activated Protein Kinases
  • Caspases
  • CBL protein, human