In vitro and in vivo radiosensitization of human glioma U251 cells induced by upregulated expression of SLC22A18.
Our previous study showed that solute carrier family 22 (organic cation transporter) member 18 (SLC22A18) downregulation via promoter methylation was associated with the development and progression of glioma, and the elevated expression of SLC22A18 was found to increase the sensitivity of glioma U251 cells to the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea. In this study, we investigated the possible upregulated expression of SLC22A18-induced enhancement of radiosensitivity of human glioma U251 cells in order to provide evidence in support of further clinical investigations. Stably overexpressing SLC22A18 human glioma U251 cells were generated to investigate the effect of SLC22A18 on the sensitivity of cells to irradiation in vitro using clonogenic survival assay. The apoptosis of U251 cells was examined with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. DNA damage and repair were measured using γH2AX foci. The effect of SLC22A18 on the in vivo tumor radiosensitivity was investigated in the orthotopic mice model. Upregulated expression of SLC22A18 enhanced the radiosensitivity of glioma U251 cells and also enhanced irradiation-induced apoptosis of U251 cells, but irradiation-induced apoptosis did not correlate with radiosensitizing effect of upregulated expression of SLC22A18. The repair of irradiation-induced double-strand-breaks was retarded in stably overexpressing SLC22A18 U251 cells. In the orthotopic mice model, the upregulated expression of SLC22A18 in U251 cells enhanced the effect of irradiation treatment and increased the survival time of mice. These results show that upregulated expression of SLC22A18 radiosensitizes human glioma U251 cells by suppressing DNA repair capacity.
Department of Neurosurgery, Shanghai 3rd People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
S-H
SH
Chu
Department of Neurosurgery, Dujiangyan Medical Center, Chengdu, China.
Z-M
ZM
Zhou
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
S
S
Karri
Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Z-Q
ZQ
Li
Department of Radiology, Shanghai 3rd People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J-M
JM
Zhao
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D011836:Radiation Tolerance; D015854:Up-Regulation
D027701:Organic Cation Transport Proteins; C111653:SLC22A18 protein, human