KRASD13 promotes apoptosis of human colorectal tumor cells by ReovirusT3D and oxaliplatin but not by tumor necrosis factor-related apoptosis-inducing ligand

Niels Smakman, Diana J.M. Van Den Wollenberg, Sjoerd G. Elias, Takehiko Sasazuki, Senji Shirasawa, Rob C. Hoeben, Inne H.M. Borel Rinkes, Onno Kranenburg

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38 Citations (Scopus)

Abstract

Colorectal tumors frequently contain activating mutations in KRAS. ReovirusT3D is an oncolytic virus that preferentially kills tumor cells with an activated Ras pathway. Here we have assessed the contribution of endogenous mutant KRAS in human colorectal cancer cell lines to ReovirusT3D replication and to tumor cell oncolysis. In addition, treatment combinations involving ReovirusT3D, oxaliplatin, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were tested for their efficacy in tumor cell killing. The mutation status of KRAS did not predict the sensitivity of a panel of human colorectal cancer cell lines to ReovirusT3D. Virus replication was observed in all cell lines tested regardless of KRAS status and was not affected by deletion of endogenous mutant KRASD13. However, deletion of KRAS D13 or p53 did reduce apoptosis induction by ReovirusT3D whereas deletion of β-cateninΔS45 had no effect. Likewise, KRASD13- or p53-deficient cells display reduced sensitivity to oxaliplatin but not to death receptor activation by TRAIL. Finally, the treatment of colorectal cancer cells with ReovirusT3D combined with either oxaliplatin or TRAIL resulted in a nonsynergistic increase in tumor cell killing. We conclude that oncolysis of human tumor cells by ReovirusT3D is not determined by the extent of virus replication but by their sensitivity to apoptosis induction. Oncogenic KRASD13 increases tumor cell sensitivity to activation of the cell-intrinsic apoptosis pathway without affecting ReovirusT3D replication.

Original languageEnglish
Pages (from-to)5403-5408
Number of pages6
JournalCancer Research
Volume66
Issue number10
DOIs
Publication statusPublished - May 15 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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