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TRAIL activates JNK and NF-κB through RIP1-dependent and -independent pathways

Laiqun Zhang1, Martin R Dittmer2, Ken Blackwell1

  • 1Department of Pathology, Carver College of Medicine, the University of Iowa, Iowa City, IA 52242, United States.

Cellular Signalling
|December 3, 2014
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can promote cancer progression by activating NF-κB. This study reveals two distinct phases of NF-κB activation by TRAIL, dependent on specific protein interactions and cellular context.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • The death receptor (DR) ligand TRAIL shows anti-cancer potential but can also promote tumor progression via NF-κB activation in resistant cells.
  • While RIP1, cFLIP, and caspase-8 are implicated, the precise mechanisms of TRAIL-induced JNK and NF-κB activation remain unclear.
  • Conflicting reports exist regarding TRAIL's effects on these pathways, necessitating mechanistic clarification.

Purpose of the Study:

  • To elucidate the underlying mechanisms of TRAIL-induced JNK and NF-κB activation in lymphoma cells.
  • To investigate the roles of RIP1, TRAF2, cIAP1/2, HOIP, cFLIP, and Bcl-2 in mediating these signaling pathways.
  • To clarify conflicting findings in the literature regarding TRAIL's dual role in cancer.

Main Methods:

  • Kinetic analysis of JNK and NF-κB pathway activation in TRAIL-sensitive lymphoma cells.
  • Examination of cells with wild-type or deficient expression of RIP1, TRAF2, cIAP1/2, or HOIP.
  • Assessment of pathway activation in cells overexpressing cFLIP or Bcl-2.

Main Results:

  • TRAIL induces two distinct phases of JNK and NF-κB activation: an early phase dependent on TRAF2/cIAP1-mediated RIP1 ubiquitination, and a delayed phase mediated by caspase-dependent MEKK1 activation.
  • cFLIP overexpression enhances the early phase but suppresses the delayed phase, while Bcl-2 overexpression promotes both phases.
  • cFLIP overexpression confers apoptosis resistance in RIP1/TRAF2-deficient cells but abrogates NF-κB activation; HOIP contributes to NF-κB activation in cFLIP-overexpressing cells.

Conclusions:

  • The study clarifies the distinct molecular mechanisms governing the early and delayed phases of TRAIL-induced JNK and NF-κB activation.
  • The findings highlight the context-dependent roles of key proteins like cFLIP and Bcl-2 in modulating TRAIL signaling.
  • This work provides a mechanistic basis for understanding TRAIL's complex effects on cancer cells and resolves conflicting previous reports.
Keywords:
ApoptosisCaspase-8NF-κBRIP1TRAILcFLIP

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