EGFR-mediated stimulation of sodium/glucose cotransport promotes survival of irradiated human A549 lung adenocarcinoma cells

Background and purpose: Solid tumor cells may adapt to an ischemic microenvironment by upregulation of sodium/glucose cotransport (SGLT) in the plasma membrane which supplies the tumor cell with glucose even at very low extracellular glucose concentration. Since SGLT activity has been shown to depend on the epithelial growth factor receptor (EGFR) and EGFR reportedly is activated by ionizing radiation, we tested for irradiation-induced SGLT activity. Materials and methods: A549 lung adenocarcinoma and FaDu head and neck squamous cancer cells were irradiated with 0 and 4 Gy X-ray and electrogenic SGLT transport activity was recorded by patch clamp current clamp in the presence and absence of extracellular glucose (5 mM), the SGLT inhibitor phlorizin (500 mu M), and the inhibitor of the EGFR tyrosine kinase activity erlotinib (1 mu M). In addition, the effect of phlorizin and erlotinib on glucose uptake and clonogenic survival was tested in irradiated and control cells by tracer flux and colony formation assays, respectively. Results: Irradiated A549 cells exhibited a significantly lower membrane potential 3 h after irradiation than the control cells. Phlorizin, erlotinib or removal of extracellular glucose, hyperpolarized the irradiated A549 cells to a significantly higher extent than the control cells. Similarly, but less pronounced, glucose removal hyperpolarized irradiated FaDu cells. In addition, irradiated A549 cells exhibited a highly increased H-3-glucose uptake which was sensitive to phlorizin. Finally, phlorizin radiosensitized the A549 and FaDu cells as evident from the colony formation assays. Conclusions: Taken together, these data suggest an irradiation-stimulated and EGFR-mediated increase in SGLT-generated glucose uptake which is required for the survival of the genotoxically stressed tumor cells. (C) 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 103 (2012) 373-379