TNFSF10 (TRAIL), a p53 target gene that mediates p53-dependent cell death

Cancer Biol Ther. 2008 Dec;7(12):2034-8. doi: 10.4161/cbt.7.12.7460.


We have identified TNFSF10 (TRAIL) as a p53-transcriptional target gene. There are two p53 DNA-binding sites in the human TNFSF10 promoter region, at 346 and 625 bp upstream of the transcription start site. A human p53-expressing adenovirus (Ad-p53) induced TRAIL mRNA and protein expression in HCT116 p53-/- human colon cancer cells. A human TRAIL-promoter reporter assay showed increased luciferase activity with the promoter vector that contains two p53 DNA-binding motifs,following Ad-p53 infection, compared to the control adenovirus infection. Using HCT116 cells, gene silencing of TNFSF10 by siRNA suppressed caspase 3 and 7 activity, even after treatment with the DNA-damaging chemotherapeutic agent adriamycin. TRAIL protein expression was elevated in adriamycin-treated breast cancer cells. In vivo, TRAIL expression was induced in mouse natural killer cells at 24 hours after systemic treatment with 5-Fluorouracil. p53-dependent TRAIL induction in natural killer cells after chemotherapy exposure provides a link between the tumor suppressor p53 and the host immune response during cancer therapy as well as a paracrine-mediated cell-extrinsic death response. Our findings provide new mechanistic insights into the signaling of p53-dependent cell death and tumor suppression, including the involvement of the host immune system and natural killer cells in vivo in the anti-tumor efficacy of chemotherapy.

MeSH terms

  • Base Sequence
  • Breast Neoplasms / genetics
  • Caspase Inhibitors
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Doxorubicin / pharmacology
  • Doxorubicin / toxicity
  • Female
  • Gene Silencing
  • HCT116 Cells
  • Humans
  • Promoter Regions, Genetic
  • TNF-Related Apoptosis-Inducing Ligand / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / physiology
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology*


  • Caspase Inhibitors
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Suppressor Protein p53
  • Doxorubicin