TY - JOUR
T1 - Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction
AU - Rouschop, Kasper M. A.
AU - Dubois, Ludwig
AU - Schaaf, Marco B. E.
AU - van den Beucken, Twan
AU - Lieuwes, Natasja
AU - Keulers, Tom G. H.
AU - Savelkouls, Kim G. M.
AU - Bussink, Johan
AU - van der Kogel, Albert J.
AU - Koritzinsky, Marianne
AU - Wouters, Bradly G.
PY - 2011/6
Y1 - 2011/6
N2 - 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 sensitivity to irradiation. Conclusions: Our results demonstrate that hypoxia induced inhibition of translational control through regulation of eIF4E is an important mediator of hypoxia tolerance and radioresistance of tumours. These data also demonstrate that deregulation of metabolic pathways such as mTOR can influence the proliferation and survival of tumour cells experiencing metabolic stress in opposite ways of nutrient replete cells.
AB - 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 sensitivity to irradiation. Conclusions: Our results demonstrate that hypoxia induced inhibition of translational control through regulation of eIF4E is an important mediator of hypoxia tolerance and radioresistance of tumours. These data also demonstrate that deregulation of metabolic pathways such as mTOR can influence the proliferation and survival of tumour cells experiencing metabolic stress in opposite ways of nutrient replete cells.
KW - eIF4E
KW - mTOR
KW - Hypoxia
KW - Necrosis
KW - Irradiation
U2 - 10.1016/j.radonc.2011.05.047
DO - 10.1016/j.radonc.2011.05.047
M3 - Article
C2 - 21665307
SN - 0167-8140
VL - 99
SP - 385
EP - 391
JO - Radiotherapy and Oncology
JF - Radiotherapy and Oncology
IS - 3
ER -