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Cap-dependent translational control of oncolytic measles virus infection in malignant mesothelioma
Blake A Jacobson1, Ahad A Sadiq1, Shaogeng Tang1
1Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Abstract:
Malignant mesothelioma has a poor prognosis for which there remains an urgent need for successful treatment approaches. Infection with the Edmonston vaccine strain (MV-Edm) derivative of measles virus results in lysis of cancer cells and has been tested in clinical trials for numerous tumor types including mesothelioma. Many factors play a role in MV-Edm tumor cell selectivity and cytopathic activity while also sparing non-cancerous cells. The MV-Edm receptor CD46 (cluster of differentiation 46) was demonstrated to be significantly higher in mesothelioma cells than in control cells. In contrast, mesothelioma cells are not reliant upon the alternative MV-Edm receptor nectin-4 for entry. MV-Edm treatment of mesothelioma reduced cell viability and also invoked apoptotic cell death. Forced expression of eIF4E or translation stimulation following IGF-I (insulin-like growth factor 1) exposure strengthened the potency of measles virus oncolytic activity. It was also shown that repression of cap-dependent translation by treatment with agents [4EASO, 4EGI-1] that suppress host cell translation or by forcing cells to produce an activated repressor protein diminishes the strength of oncolytic viral efficacy.
Insights
Measles virus therapy shows promise for malignant mesothelioma by targeting cancer cells expressing CD46. Enhancing protein translation boosts the virus
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Malignant mesothelioma has a poor prognosis, necessitating novel treatment strategies.
- Measles virus Edmonston vaccine strain (MV-Edm) demonstrates oncolytic activity against various cancers, including mesothelioma.
Purpose of the Study:
- To investigate the efficacy of MV-Edm as a treatment for malignant mesothelioma.
- To explore the role of cellular receptors and translation machinery in MV-Edm's oncolytic activity in mesothelioma.
Main Methods:
- Assessed MV-Edm receptor expression (CD46 and nectin-4) in mesothelioma cells.
- Evaluated MV-Edm's effect on mesothelioma cell viability and apoptosis.
- Investigated the impact of eIF4E expression, insulin-like growth factor 1 (IGF-I), and translation inhibitors (4EASO, 4EGI-1) on MV-Edm efficacy.
Main Results:
- Mesothelioma cells exhibit significantly higher CD46 expression compared to control cells.
- Mesothelioma cells are not dependent on nectin-4 for MV-Edm entry.
- MV-Edm treatment reduced mesothelioma cell viability and induced apoptosis.
- Enhanced eIF4E expression or IGF-I stimulation potentiated MV-Edm's oncolytic effect.
- Inhibition of host cell translation diminished MV-Edm's efficacy.
Conclusions:
- MV-Edm demonstrates oncolytic potential against malignant mesothelioma, primarily through CD46-mediated entry.
- The efficacy of MV-Edm is influenced by the host cell's translational machinery, with enhanced translation increasing potency.
- Targeting translation pathways could be a strategy to improve measles virus-based mesothelioma therapy.
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