Suppression of a DNA double-strand break repair gene, Ku70, increases radio- and chemosensitivity in a human lung carcinoma cell line.
Ku70 protein, cooperating with Ku80 and DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs), is involved in DNA double-strand break (DNA DSB) repair and V(D)J recombination. Recent studies have revealed increased ionizing radiosensitivity in Ku70-deficient cells. The presented study, using a human squamous cell lung carcinoma cell line, demonstrated that introduction of an antisense Ku70 nucleic acid made the cells more radio- and chemosensitive than the parental cells. Ku70 protein expression was suppressed in the cells with antisense Ku70 construct when compared to the wild-type cells. A relatively small but statistically significant increase in radiosensitivity of the cells was achieved by the introduction of the antisense Ku70. The increased radiosensitivity in vitro was accompanied by an approximately two-fold increase in alpha and alpha/beta values in a linear-quadratic model. The antisense Ku70 increased the chemosensitivity of the cells to some DNA-damaging agents such as bleomycin and methyl methanesulfonate, but not to cisplatin, mitomycin C, and paclitaxel. This system provides us with partial suppression of Ku70, and will be a useful experimental model for investigating the physiological roles of the DNA DSB repair gene.
Omori
Shigenari
S
Department of Respirology (B2), Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, 260-8670, Chiba, Japan.
Takiguchi
Yuichi
Y
Suda
Akira
A
Sugimoto
Takaaki
T
Miyazawa
Hiroshi
H
Takiguchi
Yasuo
Y
Tanabe
Nobuhiro
N
Tatsumi
Koichiro
K
Kimura
Hiroshi
H
Pardington
Paige E
PE
Chen
Fanqing
F
Chen
David J
DJ
Kuriyama
Takayuki
T
D034961:Antigens, Nuclear / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015152:Blotting, Northern; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D003114:Colony-Forming Units Assay; D004249:DNA Damage; D004265:DNA Helicases; D017931:DNA Primers; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D016373:DNA, Antisense / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D066298:In Vitro Techniques; D000072200:Ku Autoantigen; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014965:X-Rays
D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D017931:DNA Primers; D016373:DNA, Antisense; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen