Abstract
We have reported that DNA-dependent protein kinase (DNA-PK) activity correlates with radiation sensitivity using esophageal cancer cell lines. It has been reported that suppression of DNA-PK activity by PI3-kinase inhibitor wortmannin, antisense Ku70/DNA-PKcs or small inhibitory RNA for DNA-PKcs sensitize cells to ionizing radiation. These results indicate that levels of DNA-PK activity have relevance to cellular sensitivity to ionizing radiation. In colorectal cancer, DNA-PK activity and protein/mRNA levels of Ku70, Ku80, DNA-PKcs and Sp1 were significantly higher in the tumor tissues compared with the normal tissues. Ku70, Ku80 and DNA-PKcs have consensus Sp1 recognition elements in their promoter region, which suggest their transcription is Sp1-dependent. In esophageal cancer, DNA-PK activity and protein/mRNA levels of Ku70, Ku80, DNA-PKcs and Sp1 were significantly higher in the tumor tissues compared with the normal tissues. In immunohistochemical analysis, DNA-PKcs, Ku80 and Ku70 were expressed almost exclusively in the nuclei. In normal squamous epithelium, the cells in basal cell layer highly expressed them and the differentiated cells express them at low intensity. Their expression varies in the same cancer tissue, which makes the estimation of radiation sensitivity by biopsy difficult. For radio-sensitization of tumor tissue, we found that phosphorothioate oligonucleotides and suramin inhibit DNA-PK activity. Suramin is supposed to be applicable to clinical use.
