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TRAIL resistance results in cancer progression: a TRAIL to perdition?

H Malhi1, G J Gores

  • 1Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Oncogene
|June 21, 2006
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise against cancer but faces resistance. TRAIL-resistant cells activate NF-kappaB, promoting tumor spread, suggesting combination therapies may be more effective.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces cancer cell death.
  • TRAIL resistance limits its therapeutic potential.
  • TRAIL resistance unmasks alternative signaling pathways.

Purpose of the Study:

  • To investigate the mechanisms of TRAIL resistance.
  • To explore alternative signaling pathways activated by TRAIL in resistant cells.
  • To propose rational combination therapies for cancer treatment.

Main Methods:

  • Analysis of TRAIL signaling pathways in cancer cells.
  • Investigation of molecular mechanisms underlying TRAIL resistance.
  • Evaluation of nuclear factor-kappaB (NF-kappaB) activation in TRAIL-resistant cells.

Main Results:

  • TRAIL-resistant cells exhibit predominant activation of NF-kappaB upon TRAIL receptor activation.
  • NF-kappaB activation promotes tumor metastasis and invasion.
  • TRAIL resistance mechanisms include upregulation of cFLIP or increased Bcl-2 family antiapoptotic proteins.

Conclusions:

  • TRAIL resistance involves alternative signaling through NF-kappaB.
  • Targeting NF-kappaB, cFLIP, or Bcl-2 family proteins in combination with TRAIL may overcome resistance.
  • Combination therapy represents a more rational approach than TRAIL alone for cancer treatment.

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