Dual role of DR5 in death and survival signaling leads to TRAIL resistance in cancer cells

Cell Death Dis. 2017 Aug 31;8(8):e3025. doi: 10.1038/cddis.2017.423.


Besides its tumor-selective apoptotic activity, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes pro-survival, proliferative or migratory signaling (NF-κB, PI3K/Akt, MAPK and JNK; referred to as 'non-apoptotic' cascades). Indeed, apoptosis and non-apoptotic signaling can be activated in clonal populations of cancer cells in response to treatment and, as a result, only a part of the initial cellular population dies while a fraction survives and develops resistance to TRAIL-induced apoptosis (referred to as 'fractional survival'). Notably, the molecular characterization of the protein platforms streaming into tumoricidal versus tumor-promoting cascades that control fractional survival remained elusive. Here we demonstrate that, in the context of DR4-DR5-DcR2 hetero-oligomeric complexes, a single death receptor (DR5) suffices to assemble composite plasma membrane-proximal pro-apoptotic/pro-survival platforms that propagate TRAIL signaling to both death and survival pathways in clonal populations of cancer cells. Moreover, we show that while all members of TRAIL-induced complexes support survival, none of them acted exclusively pro-apoptotic. Indeed, key apoptotic proteins as FADD and procaspase-8 were also involved in transducing non-apoptotic signaling in response to this cytokine. Collectively, this study reveals the Janus faces of DR5, and the contributions of other death complex components in fractional survival that foster the generation of resistance. Our data highlight a new level of complexity in TRAIL signaling and point to an improved therapeutic rationale in view of hitherto disappointing results.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cell Line, Transformed
  • Cell Survival / drug effects
  • Clone Cells
  • Drug Resistance, Neoplasm / genetics*
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology*
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Tumor Necrosis Factor Decoy Receptors / genetics
  • Tumor Necrosis Factor Decoy Receptors / metabolism


  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • NF-kappa B
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFRSF10D protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor Decoy Receptors
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Caspase 8