Cisplatin-dependent upregulation of death receptors 4 and 5 augments induction of apoptosis by TNF-related apoptosis-inducing ligand against esophageal squamous cell carcinoma

Int J Cancer. 2006 Jan 1;118(1):230-42. doi: 10.1002/ijc.21283.


TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily known to induce apoptosis in a variety of cancers. The purpose of our study was to examine the effects of TRAIL in combination with cisplatin against esophageal squamous cell carcinoma (ESCC) cell lines in vitro and in vivo, and to elucidate underlying molecular mechanisms. Expression profiles of TRAIL receptors were investigated in 19 ESCC (KYSE) cell lines using RT-PCR. Crystal violet staining assays were performed to reveal the sensitivity against TRAIL. Flow cytometric analyses of apoptosis induction and TRAIL receptor expression were performed. Furthermore, Western blot was used to clarify the apoptosis pathway involved, and a nude-mouse xenograft model was used to show effects in vivo. Results show that death receptors (DR) 4 and 5 were expressed in 100% of the cell lines, and 79% (15/19) expressed 4 TRAIL receptors. There was only 1 cell line without decoy receptor expression. Eighteen cell lines were resistant to TRAIL, but in some, the combination treatment with cisplatin could overcome this resistance. They underwent apoptosis via activation of caspase-8 and -3, and cisplatin-dependent upregulation of DR4 and 5 was detected. Furthermore, pretreatment with cisplatin followed by TRAIL resulted in significant tumoricidal effects. Finally, systemic administration of TRAIL with cisplatin synergistically suppressed tumor growth of ESCC xenografts in nude mice. These results provide a significance of cisplatin-induced upregulation of death receptors as apoptosis-inducing machinery, and it was suggested that sequential administration of cisplatin and TRAIL might be a feasible chemotherapeutic regimen against ESCC.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology*
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology*
  • Flow Cytometry
  • Gene Expression Profiling
  • Humans
  • Membrane Glycoproteins
  • Mice
  • Mice, Nude
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / biosynthesis*
  • Reverse Transcriptase Polymerase Chain Reaction
  • TNF-Related Apoptosis-Inducing Ligand
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha
  • Up-Regulation


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tnfrsf10b protein, mouse
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Cisplatin