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

T. J. Kemp, J. S. Kim, S. A. Crist, Thomas S. Griffith

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)587-599
Number of pages13
JournalApoptosis
Volume8
Issue number6
DOIs
StatePublished - Dec 2003

Bibliographical note

Funding Information:
This work was supported by an American Cancer Society Institutional Seed Grant (#IN-122U) administered through University of Iowa’s Holden Comprehensive Cancer Center, the Edwin Beer Program of The New York Academy of Medicine, and a Department of Defense Prostate Cancer Research Program New Investigator Award (PC010599).

Keywords

  • Adenovirus
  • Apoptosis
  • Necrosis
  • TRAIL/Apo2L;
  • Tumor

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