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M404541200v1
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Papers In Press, published online ahead of print June 28, 2004
J. Biol. Chem, 10.1074/jbc.M404541200
Submitted on April 23, 2004
Revised on June 28, 2004
Accepted on June 28, 2004

Death induction by recombinant native TRAIL and its prevention by a caspase 9 inhibitor in primary human esophageal epithelial cells

Seok-Hyun Kim, Kunhong Kim, Jae G. Kwagh, David T. Dicker, Meenhard Herlyn, Anil K. Rustgi, Youhai Chen, and Wafik S. El-Deiry

University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Corresponding Author: wafik{at}mail.med.upenn.edu

The cytotoxic death ligand TRAIL (TNF-Related Apoptosis Inducing Ligand) is a tumor-specific agent under development as a novel anticancer therapeutic. However, some reports have demonstrated toxicity of certain TRAIL preparations towards human hepatocytes and keratinocytes through a caspase-dependent mechanism that involves activation of the extrinsic death pathway and Type II signaling through the mitochondria. We have isolated and purified both His-tagged and 3 versions of native recombinant human TRAIL protein from E. coli. We found that 5 mM DTT in the purification process enhanced oligomerization of TRAIL and resulted in the formation of hyper-oligomerized TRAILs, including hexamers and nonomers with an extremely high potency in apoptosis induction. Whereas DISC formation was much more efficient in cells treated with hyper-oligomerized TRAILs, this did not convert TRAIL-sensitive Type II HCT116 colon tumor cells to a Type I death pattern as judged by their continued sensitivity to a caspase 9 inhibitor. Moreover, TRAIL-resistant Type II Bax-null colon carcinoma cells were not converted to a TRAIL-sensitive Type I state by hyper-oligomerized TRAIL. Primary human esophageal epithelial (EPC2) cells were found to be sensitive to all TRAIL preparations used, including trimer TRAIL. TRAIL induced death in EPC2 cells was prevented by caspase 9 inhibition up to 4 hours after TRAIL exposure. This result suggests a possible therapeutic application of caspase 9 inhibition as a strategy to reverse TRAIL toxicity. Hyper-oligomerized TRAIL may be considered as an alternative agent for testing in clinical trials.


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