Abstract
Heat-shock protein 90 (Hsp90) is a ubiquitous molecular chaperone protein, which is related to the stabilization and activation of various cell cycle checkpoints and signal transduction proteins. Insulin-like growth factor I receptor (IGF-IR) overexpressed HeLa cells (HeLa-IGF-IR) exhibited a radioresistant phenotype. We have studied the radiosensitization effects of an HSP90 inhibitor 17AAG in HeLa-IGF-IR cells. After pretreatment with 17-AAG for 24 hours, cellular radiosensitivities were studied with colony-forming assay, MTT assay, western blotting, SLGA, and immunostaining.
150nM of 17AAG pretreatment significantly radio-sensitized HeLa-IGF-IR cells, but this sensitization was not observed with non-transfected HeLa cells. Protein expression of PARP after irradiation was reduced with the 17-AAG pretreatment, indicating apoptosis formation. X-irradiation with 17-AAG pretreatment in HeLa-IGF-IR cells led to reduction in cell growth kinetics, spheroid formation prevention, and hyper-sensitivity for gamma-H2AX and p-ATM foci formation when compared to HeLa cells. The downstream pathways of IGF-IR (PI3-K/Akt and Raf/MEK/ERK pathways, proliferation signal pathways) were inhibited by 17AAG treatment, and more cells were led to apoptosis and SLGA. 17AAG treatment would be a novel method for certain radio-resistant tumor cells.
