Enhancement of radiosensitivity by 5-Aza-CdR through activation of G2/M checkpoint response and apoptosis in osteosarcoma cells.
Radiation resistance is a major problem preventing successful treatment. Therefore, identifying sensitizers is vitally important for radiotherapy success. Epigenetic events such as DNA methylation have been proposed to mediate the sensitivity of tumor therapy. In this study, we investigated the influence of demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) on the radiosensitivity of human osteosarcoma cell lines. 5-Aza-CdR was capable of sensitizing three osteosarcoma cells to irradiation in a time-dependent manner, with the maximum effect attained by 48 h. Pretreatment with 5-Aza-CdR synchronized cells in G2/M phase of the cell cycle and enhanced irradiation-induced apoptosis compared with irradiation alone in SaOS2, HOS, and U2OS cells. Moreover, 5-Aza-CdR restored mRNA expressions of 14-3-3σ, CHK2, and DAPK-1 in the three cells, accompanied with demethylation of their promoters. These findings demonstrate that demethylation with 5-Aza-CdR increases radiosensitivity in some osteosarcoma cells through arresting cells at G2/M phase and increasing apoptosis, which is partly mediated by upregulation of 14-3-3σ, CHK2, and DAPK-1 genes, suggesting that 5-Aza-CdR may be a potential radiosensitizer to improve the therapy effect in osteosarcoma.
Key Laboratory of Oncology, Cancer Center, Division of Internal Medicine, Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, 100853, China.
Yi
Y
Li
PeiLiang
P
Geng
Weihao
W
Jiang
Yunlai
Y
Wang
Jie
J
Yao
Xu
X
Lin
Jun
J
Liu
Lichun
L
Huang
Bin
B
Su
Hong
H
Chen
D048948:14-3-3 Proteins / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics; D001859:Bone Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000235:genetics; D064550:Death-Associated Protein Kinases / Q000235:genetics; D000077209:Decitabine; D005095:Exoribonucleases / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D012516:Osteosarcoma / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance
D048948:14-3-3 Proteins; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D000077209:Decitabine; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D005095:Exoribonucleases; C413442:SFN protein, human; D001374:Azacitidine