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 p16(ink4a), one of the major tumor suppressor proteins that regulate the cell cycle. We hypothesized that the absence of p16(ink4a) contributes to the intrinsic radiation resistance of chondrosarcomas and that restoring p16(ink4a) expression would increase their radiation sensitivity. To test this we determined the effects of ectopic p16(ink4a) expression on chondrosarcoma cell resistance to low-dose gamma-irradiation (1-5 Gy). p16(ink4a) expression significantly increased radiation sensitivity in clonogenic assays. Apoptosis did not increase significantly with radiation and was unaffected by p16(ink4a) transduction of chondrosarcoma cells, indicating that mitotic catastrophe, rather than programmed cell death, was the predominant radiation effect. These results support the hypothesis that p16(ink4a) 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.
Moussavi-Harami
Farid
F
Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, 52242, USA.
Mollano
Anthony
A
Martin
James A
JA
Ayoob
Andrew
A
Domann
Frederick E
FE
Gitelis
Steven
S
Buckwalter
Joseph A
JA
D000165:Acridine Orange / Q000494:pharmacology; D017209:Apoptosis / Q000528:radiation effects*; D001859:Bone Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D002813:Chondrosarcoma / Q000378:metabolism / Q000532:radiotherapy*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D005720:Gamma Rays; D006801:Humans; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D011838:Radiation-Sensitizing Agents; D000165:Acridine Orange