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

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Abstract

A great deal of enthusiasm is being generated for TRAIL (TNF-related apoptosis-inducing ligand)/Apo-2L as a tumor therapeutic agent because it is cytotoxic to a variety of tumor cell types but not normal cells. Moreover, it is well documented that TRAIL/Apo-2L-induced tumor cell death is a caspase-dependent apoptotic process. Through the use of a transfected cell line expressing murine TRAIL/Apo-2L and a recombinant adenovirus encoding the murine TRAIL/Apo-2L cDNA (Ad5-mTRAIL) against two murine tumor cell lines [TRAMP-C2 (prostate adenocarcinoma) and Renca (renal adenocarcinoma)], we found that mTRAIL/Apo-2L also can kill tumor cells by inducing necrosis. Specifically, we observed the default method of mTRAIL/Apo-2L-induced death in TRAMP-C2 cells was via a necrotic process, characterized by the complete lack of an annexin V+/PI− population, SAPK/JNK phosphorylation, caspase activation, Bid cleavage, or cytochrome c release. Moreover, the inclusion of zVAD-fmk, an inhibitor of caspase activation, markedly enhanced mTRAIL/Apo-2L-mediated killing of TRAMP-C2. In contrast, apoptosis was induced in TRAMP-C2 using TNF, as measured by the criteria listed above, as was Renca by mTRAIL/Apo-2L. These results demonstrate the natural occurrence of both TRAIL/Apo-2L-induced apoptotic and necrotic signaling mechanisms within tumor cells.

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Authors and Affiliations

  1. Department of Urology, USA

    T. J. Kemp, S. A. Crist & T. S. Griffith

  2. Interdisciplinary Graduate Program in Immunology, University of Iowa, 375 Newton Road, Iowa City, IA, 52242-1089, USA

    T. J. Kemp & S. A. Crist

  3. Department of Urology, University of Iowa, 375 Newton Road, Iowa City, IA, 52242-1089, USA

    J.-S. Kim

  4. Prostate Cancer Research Group, USA

    T. S. Griffith

  5. Interdisciplinary Graduate Program in Immunology, USA

    T. S. Griffith

  6. The Holden Comprehensive Cancer Center, University of Iowa, 375 Newton Road, Iowa City, IA, 52242-1089, USA

    T. S. Griffith

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  1. T. J. Kemp
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Kemp, T.J., Kim, JS., Crist, S.A. et al. Induction of necrotic tumor cell death by TRAIL/Apo-2L. Apoptosis 8, 587–599 (2003). https://doi.org/10.1023/A:1026286108366

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