Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells
| Autor: | Cay Egan, Patrick W. K. Lee, Peter A. Forsyth, Stefan J. Urbanski, Tommy Alain, Manbok Kim, Randal N. Johnston |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Fibrosarcoma viruses Oncogene Protein p21(ras) Biology Gene mutation Reoviridae medicine.disease_cause Cathepsin B Cell Line Viral entry Cell Line Tumor Genetics medicine Humans Molecular Biology DNA Primers Base Sequence medicine.disease Virology Oncolytic virus Cell culture Apoptosis Mutation Cancer research HT1080 Carcinogenesis |
| Zdroj: | Oncogene. 26:4124-4134 |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Reovirus shows considerable potential as an oncolytic agent for Ras-activated tumors and is currently in clinical trials. Here we ask whether such tumor cell lines can acquire resistance to reoviral oncolysis. We challenged human HT1080 fibrosarcoma cells that carry a Ras mutation by prolonged exposure to reovirus, thereby yielding highly virus-resistant HTR1 cells. These cells are persistently infected with reovirus, exhibit high Ras activity and retain the original Ras gene mutation, showing that resistance to reovirus can be displayed in cells with active Ras. The HTR1 cells also exhibit reduced cellular cathepsin B activity, which normally contributes to viral entry and activation. Persistently infected HTR1 cells were not tumorigenic in vivo, whereas immunologically cured virus-free HTR1 cells were highly tumorigenic. Thus, acquisition of resistance to reovirus may constrain therapeutic strategies. To determine whether reoviral resistance is associated with a general reduction in apoptotic potential, we challenged the HTR1 cells with apoptotic inducers and E1B-defective adenovirus, resulting in significant apoptosis and cell death following both approaches. Therefore, even if resistance to reoviral oncolysis should arise in tumor cells in vivo, other therapeutic strategies may nevertheless remain effective. |
| Databáze: | OpenAIRE |
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