Intrinsic radiation resistance in human chondrosarcoma cells

Human chondrosarcomas rarely respond to radiation treatment, limiting the options for eradication of these tumors. The basis of radiation resistance in chondrosarcomas remains obscure. In normal cells radiation induces DNA damage that leads to growth arrest or death. However, cells that lack cell cycle control mechanisms needed for these responses show intrinsic radiation resistance. In previous work, we identified immortalized human chondrosarcoma cell lines that lacked p16ink4a, one of the major tumor suppressor proteins that regulate the cell cycle. We hypothesized that the absence of p16ink4a contributes to the intrinsic radiation resistance of chondrosarcomas and that restoring p16ink4a expression would increase their radiation sensitivity. To test this we determined the effects of ectopic p16ink4a expression on chondrosarcoma cell resistance to low-dose γ-irradiation (1–5 Gy). p16ink4a expression significantly increased radiation sensitivity in clonogenic assays. Apoptosis did not increase significantly with radiation and was unaffected by p16ink4a transduction of chondrosarcoma cells, indicating that mitotic catastrophe, rather than programmed cell death, was the predominant radiation effect. These results support the hypothesis that p16ink4a plays a role in the radiation resistance of chondrosarcoma cell lines and suggests that restoring p16 expression will improve the radiation sensitivity of human chondrosarcomas.