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Journal of Virology, December 2005, p. 14981-14985, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14981-14985.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Sensitization to Apoptosis Underlies Kras^D12-Dependent Oncolysis of Murine C26 Colorectal Carcinoma Cells by Reovirus T3D

Department of Surgery, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht,¹ Virus and Stem Cell Biology Lab, Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden, The Netherlands²

Received 17 August 2005/ Accepted 14 September 2005

Reovirus T3D is an oncolytic agent that preferentially targets tumor cells expressing an activated Ras oncogene. Ras signaling interferes with the cellular stress response that inhibits translation of reovirus RNAs. Murine C26 colorectal carcinoma cells express a mutant Kras^D12 gene. Reovirus T3D efficiently kills C26 cells, but not C26 cells in which the Kras^D12 mRNA is stably repressed by expression of Kras^D12-directed short-hairpin RNAs. Surprisingly, neither reovirus T3D protein synthesis nor T3D virus yields were suppressed by deletion of Kras^D12. Rather, reovirus-induced tumor cell apoptosis was completely abrogated as a result of Kras knockdown. We conclude that sensitization of C26 tumor cells to reovirus-induced apoptosis underlies the Ras dependency of reovirus T3D oncolysis.

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