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Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction

Kasper M. A. Rouschop, Ludwig Dubois, Marco B. E. Schaaf, Twan van den Beucken, Natasja Lieuwes, Tom G. H. Keulers, Kim G. M. Savelkouls, Johan Bussink, Albert J. van der Kogel, Marianne Koritzinsky, Bradly G. Wouters
 

Background and purpose:

Tumour hypoxia is an important limiting factor in the successful treatment of cancer. Adaptation to hypoxia includes inhibition of mTOR, causing scavenging of eukaryotic initiation factor 4E (eIF4E), the rate-limiting factor for cap-dependent translation. The aim of this study was to determine the effect of preventing mTOR-dependent translation inhibition on hypoxic cell survival and tumour sensitivity towards irradiation.

Material and methods:

The effect of eIF4E-overexpression on cell proliferation, hypoxia-tolerance, and radiation sensitivity was assessed using isogenic, inducible U373 and HCT116 cells.

Results:

We found that eIF4E-overexpression significantly enhanced proliferation of cells under normal conditions, but not during hypoxia, caused by increased cell death during hypoxia. Furthermore, eIF4E- overexpression stimulated overall rates of tumour growth, but resulted in selective loss of hypoxic cells in established tumours and increased levels of necrosis. This markedly increased overall tumour sensitiv- ity to irradiation.

Journal: Radiotherapy and Oncology, no. 99, 2011