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TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5

Johannes Lemke1, Andreas Noack, Dieter Adam

  • 1Division of Molecular Oncology, Institute of Experimental Cancer Research, Comprehensive Cancer Center North, UK S-H, Arnold-Heller Str. 3, Haus 17, 24 105 Kiel, Germany.

Journal of Molecular Medicine (Berlin, Germany)
|April 1, 2010
PubMed

Insights

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and its antibodies activate cell death signaling. TRAIL primarily uses DR4, while DR5 is silenced for TRAIL but not antibody treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • TRAIL (Tumor necrosis factor related apoptosis-inducing ligand) and agonistic antibodies targeting DR4/TRAIL-R1 and DR5/TRAIL-R2 are investigated for cancer therapy.
  • TRAIL activates DR4 and DR5, initiating apoptotic and non-apoptotic pathways, but their distinct roles remain unclear.

Purpose of the Study:

  • To compare the effects of TRAIL, anti-DR4 (mapatumumab), and anti-DR5 (lexatumumab) antibodies on pancreatic ductal adenocarcinoma cells.
  • To elucidate the differential roles of DR4 and DR5 in mediating cell death and inflammatory signaling.

Main Methods:

  • Analysis of cell viability, Death-Inducing Signaling Complex (DISC) formation, and IL-8/NF-kappaB activation.
  • Use of DR4- and DR5-specific Fab fragments for receptor blocking.
  • Inhibition of Protein Kinase C (PKC) using Goe6983.

Main Results:

  • TRAIL, mapatumumab, and lexatumumab activated cell death and pro-inflammatory signaling.
  • Mapatumumab and lexatumumab induced DR4 or DR5 homocomplexes, while TRAIL induced heterocomplexes.
  • TRAIL predominantly signaled via DR4; DR5 could trigger apoptosis with TRAIL upon PKC inhibition, and lexatumumab-mediated cell death was enhanced.

Conclusions:

  • TRAIL primarily signals through DR4, with mechanisms silencing DR5 for TRAIL-induced apoptosis but not for antibody treatment.
  • Agonistic antibodies activate DR4 and DR5 independently of TRAIL's signaling pathway.
  • Targeting DR4 and DR5 offers distinct therapeutic strategies in pancreatic cancer.

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