Death Receptor 4 (DR4) Efficiently Kills Breast Cancer Cells Irrespective of Their Sensitivity to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)

Cancer Gene Ther. 2004 Oct;11(10):691-8. doi: 10.1038/sj.cgt.7700747.

Abstract

Breast cancer cells are generally resistant to induction of apoptosis by treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we demonstrate that both TRAIL-sensitive and TRAIL-resistant breast cancer cell lines can be efficiently killed by overexpression of the TRAIL receptor, death receptor 4 (DR4). The extent of cell death depended on the strength of the promoter driving DR4 expression. When driven by the strong CMV promoter, expression of DR4 killed over 90% of cells in five out of six cell lines tested in the absence of exogenous TRAIL. When driven by the relatively weak tumor-specific hTERT promoter, DR4 was less effective alone, but sensitized cells to killing by TRAIL. The extent of TRAIL sensitization depended on the magnitude of hTERT promoter activity. MCF-7 cells were relatively resistant to the action of DR4. We compared expression of the genes involved in transduction and execution of the death receptor-initiated apoptotic stimuli between MCF-7 and DR4-sensitive cell lines. We confirmed that in the panel of cell lines, MCF-7 was the only line deficient in expression of caspase 3. Bcl-2 and FLIP proteins, implicated in suppression of TRAIL-induced apoptosis, were expressed at a higher level.

Publication types

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

MeSH terms

  • Annexin A5 / analysis
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Caspase 3
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cytomegalovirus / genetics
  • DNA-Binding Proteins
  • Drug Resistance, Neoplasm
  • Female
  • Flow Cytometry
  • Gene Expression*
  • Genetic Vectors
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Glycoproteins / pharmacology*
  • Nuclease Protection Assays
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / physiology*
  • TNF-Related Apoptosis-Inducing Ligand
  • Telomerase / genetics
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Annexin A5
  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Telomerase
  • CASP3 protein, human
  • Caspase 3
  • Caspases