Department of Radiation Oncology (Maastro Lab), Maastricht University, The Netherlands.
Radiother Oncol. 2011 Jun;99(3):385-91. doi: 10.1016/j.radonc.2011.05.047. Epub 2011 Jun 12.
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.
The effect of eIF4E-overexpression on cell proliferation, hypoxia-tolerance, and radiation sensitivity was assessed using isogenic, inducible U373 and HCT116 cells.
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.
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.
肿瘤缺氧是癌症成功治疗的一个重要限制因素。对缺氧的适应包括抑制 mTOR，导致真核起始因子 4E（eIF4E）的清除，这是帽依赖性翻译的限速因子。本研究的目的是确定防止 mTOR 依赖性翻译抑制对缺氧细胞存活和肿瘤对辐射敏感性的影响。
使用同基因诱导型 U373 和 HCT116 细胞，评估 eIF4E 过表达对细胞增殖、缺氧耐受性和辐射敏感性的影响。
我们发现，eIF4E 过表达显著增强了正常条件下细胞的增殖，但在缺氧条件下却没有，这是由于缺氧期间细胞死亡增加所致。此外，eIF4E 过表达刺激了肿瘤的总体生长速度，但在已建立的肿瘤中导致缺氧细胞选择性丢失，并增加了坏死水平。这明显增加了肿瘤对辐射的整体敏感性。
我们的结果表明，通过调节 eIF4E 诱导的翻译控制抑制是肿瘤缺氧耐受性和放射抗性的重要介导因素。这些数据还表明，代谢途径如 mTOR 的失调可以以与营养充足的细胞相反的方式影响经历代谢应激的肿瘤细胞的增殖和存活。
