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Modeling Chemotherapy Resistant Leukemia In Vitro
08:41

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Published on: February 9, 2016

Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level

A Morizot1, D Mérino, N Lalaoui

  • 1INSERM, U866, Dijon, F-21079 France [2] Faculty of Medicine and Pharmacy, Université de Bourgogne, Dijon, F-21079, France.

Cell Death and Differentiation
|November 13, 2010
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell death. However, TRAIL receptor 4 (TRAIL-R4) inhibits this process, but chemotherapy can restore TRAIL

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • TNF-related apoptosis-inducing ligand (TRAIL) targets cancer cells by inducing apoptosis via TRAIL-R1/R2.
  • TRAIL also binds TRAIL receptor 4 (TRAIL-R4), with its role in apoptosis inhibition being debated.

Purpose of the Study:

  • To investigate the inhibitory role of TRAIL-R4 in TRAIL-induced apoptosis.
  • To explore therapeutic strategies to overcome TRAIL-R4-mediated resistance in cancer treatment.

Main Methods:

  • Assessing apoptosis in cells expressing TRAIL-R4.
  • Evaluating the effect of combining TRAIL with chemotherapeutic drugs.
  • Analyzing DISC formation, caspase-8 activation, and mitochondrial pathways.
  • Assessing tumor regression in a mouse model.

Main Results:

  • TRAIL-R4 expression inhibits TRAIL-induced apoptosis in tumor cells.
  • Chemotherapy restores TRAIL sensitivity in TRAIL-R4-expressing cells by enhancing DISC-level caspase-8 activation.
  • TRAIL-R4 cooperates with c-FLIP to suppress apoptosis, independent of mitochondrial pathways.
  • TRAIL-R4 hinders TRAIL-mediated tumor regression in vivo, which can be rescued by chemotherapy.

Conclusions:

  • TRAIL-R4 acts as a negative regulator of TRAIL signaling.
  • Combining TRAIL with chemotherapy is a viable strategy to overcome TRAIL-R4-mediated resistance and promote tumor regression.

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