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The tumour microenvironment is characterised by oxygen, glucose and nutrient deprivation. The unfoldedprotein response (UPR), a stress response activated by nutrient and oxygen deprivation facilitates cell survival. The UPR enhances chemoresistance but little is known about its interaction with radiotherapy. The aim of this study was to establish if UPR activation interacts with radiosensitivity in colorectal cancer cells.A model of UPR induction in vitro was developed in HT29 cells by exposure to hypoglycaemic media. UPR induction was confirmed by over expression of the UPRprotein, GRP78, with western blotting. Normal or UPR induced cells were then exposed to an LD50 (1.5 Gy) or LD90 (4 Gy) dose of radiotherapy. Relative percentage survival was determined by clonogenic assay.Hypoglycaemia activates the UPR in-vitro. UPR activation in HT29 cells significantly decreased their sensitivity to both the LD50 and LD90 doses of radiation, (% survival at 1.5 Gy 68.14% standard media vs 82.59% 1 mmol glucose media and at 4 Gy 27.6% standard media vs 38.3% 1 mmol glucose media; P < 0.05).UPR induction may enhance the radioresistance of colorectal cancer cells in-vitro. Further in-vivo research is indicated to explore its clinical significance.