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Induction of necrotic tumor cell death by TRAIL/Apo-2L

T J Kemp1, J-S Kim, S A Crist

  • 1Department of Urology, Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242-1089, USA.

Apoptosis : an International Journal on Programmed Cell Death
|January 24, 2004
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce both apoptosis and necrosis in cancer cells. This study reveals that TRAIL/Apo-2L triggers necrotic cell death in some tumor types, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Mechanisms

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L is a promising cancer therapeutic due to its selective tumor cell cytotoxicity.
  • TRAIL/Apo-2L-induced cell death is typically characterized as a caspase-dependent apoptotic process.

Purpose of the Study:

  • To investigate the mechanisms of cell death induced by murine TRAIL/Apo-2L (mTRAIL/Apo-2L) in murine tumor cell lines.
  • To determine if mTRAIL/Apo-2L can induce necrotic cell death in addition to apoptosis.

Main Methods:

  • Utilized a transfected cell line expressing mTRAIL/Apo-2L and a recombinant adenovirus encoding mTRAIL/Apo-2L (Ad5-mTRAIL).
  • Tested mTRAIL/Apo-2L efficacy against TRAMP-C2 (prostate adenocarcinoma) and Renca (renal adenocarcinoma) cell lines.
  • Assessed cell death pathways by analyzing annexin V/PI staining, SAPK/JNK phosphorylation, caspase activation, Bid cleavage, and cytochrome c release.
  • Investigated the effect of zVAD-fmk, a caspase inhibitor, on mTRAIL/Apo-2L-mediated cell killing.

Main Results:

  • mTRAIL/Apo-2L induced necrotic cell death in TRAMP-C2 cells, characterized by the absence of typical apoptosis markers.
  • Necrotic cell death in TRAMP-C2 cells showed no caspase activation, Bid cleavage, or cytochrome c release.
  • Caspase inhibition with zVAD-fmk enhanced mTRAIL/Apo-2L-mediated killing of TRAMP-C2 cells.
  • Apoptosis was induced in TRAMP-C2 cells by TNF and in Renca cells by mTRAIL/Apo-2L.

Conclusions:

  • Demonstrates that TRAIL/Apo-2L can naturally induce both apoptotic and necrotic signaling pathways in tumor cells.
  • Highlights the potential for targeting both death pathways for effective cancer therapy.

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