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Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis

M Hörnle1, N Peters, B Thayaparasingham

  • 1Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Baden-Württemberg, Germany.

Oncogene
|September 22, 2010
PubMed

Insights

Ultraviolet (UV) B light combined with tumor necrosis factor related apoptosis inducing ligand (TRAIL) therapy sensitizes melanoma cells. UVB triggers caspase-3 to cleave X-linked inhibitor of apoptosis protein (XIAP), enhancing TRAIL-induced apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Melanoma metastasis is challenging due to chemoresistance and radioresistance.
  • Combinational treatments involving death ligands are crucial for effective melanoma therapy.
  • Melanoma cell resistance to tumor necrosis factor related apoptosis inducing ligand (TRAIL) is often mediated by X-linked inhibitor of apoptosis protein (XIAP).

Purpose of the Study:

  • To elucidate the molecular mechanism by which ultraviolet (UV) B irradiation sensitizes melanoma cells to TRAIL.
  • To identify the specific caspase responsible for X-linked inhibitor of apoptosis protein (XIAP) cleavage after UVB treatment.
  • To explore the broader implications of this mechanism in melanoma treatment.

Main Methods:

  • Treatment of melanoma cell lines with TRAIL and sub-lethal ultraviolet (UV) B irradiation.
  • Assessment of X-linked inhibitor of apoptosis protein (XIAP) levels and caspase-3 processing.
  • Utilization of caspase inhibitors and small interfering RNA (siRNA) for knockdown studies.
  • Analysis of mitochondrial outer membrane permeabilization and Smac release.

Main Results:

  • Co-irradiation with ultraviolet (UV) B caused X-linked inhibitor of apoptosis protein (XIAP) depletion, synergistically sensitizing melanoma cells to tumor necrosis factor related apoptosis inducing ligand (TRAIL).
  • X-linked inhibitor of apoptosis protein (XIAP) depletion requires initial caspase-mediated cleavage, promoting its proteasomal degradation.
  • Caspase-3 was identified as the primary caspase responsible for cleaving X-linked inhibitor of apoptosis protein (XIAP) after UVB treatment, leading to its activation and subsequent apoptosis.
  • Ultraviolet (UV) B and TRAIL co-treatment accelerated mitochondrial outer membrane permeabilization, releasing Smac and other XIAP antagonists.

Conclusions:

  • Ultraviolet (UV) B irradiation sensitizes melanoma cells to TRAIL by inducing caspase-3-mediated cleavage and degradation of X-linked inhibitor of apoptosis protein (XIAP).
  • This mechanism involves caspase-3 activation, accelerated mitochondrial outer membrane permeabilization, and release of XIAP-antagonizing factors.
  • The discovered molecular mechanism of X-linked inhibitor of apoptosis protein (XIAP) cleavage has potential implications for other chemo-sensitization strategies in melanoma.

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