Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities

Abstract

Abstract.The variability of radiation responses in ovarian tumors and tumor-derived cell lines is poorly understood. Since both DNA repair capacity and p53 status can significantly alter radiation sensitivity, we evaluated these factors along with radiation sensitivity in a panel of sporadic human ovarian carcinoma cell lines. We observed a gradation of radiation sensitivity among these sixteen lines, with a five-fold difference in the LD 50 between the most radiosensitive and the most radioresistant cells. The DNA-dependent protein kinase (DNA-PK) is essential for the repair of radiation induced DNA double-strand breaks in human somatic cells. Therefore, we measured gene copy number, expression levels, protein abundance, genomic copy and kinase activity for DNA-PK in all of our cell lines. While there were detectable differences in DNA-PK between the cell lines, there was no clear correlation with any of these differences and radiation sensitivity. In contrast, p53 function as determined by two independent methods, correlated well with radiation sensitivity, indicating p53 mutant ovarian cancer cells are typically radioresistant relative to p53 wild-type lines. These data suggest that the activity of regulatory molecules such as p53 may be better indicators of radiation sensitivity than DNA repair enzymes such as DNA-PK in ovarian cancer.

Mutual regulation between DNA-PKcs and snail1 leads to increased genomic instability and aggressive tumor characteristics

“…Indeed, there is research reporting that decrease of single DNA-PKcs activity was not a major factor for damage sensitivity. 23, 24 Another interpretation is that DNA-PKcs-mediated phosphorylation of p53, a substrate of DNA-PKcs, 21, 25, 26, 27, 28 was decreased by Snail1 overexpression. Therefore, decreased p53 function by Snail1 may be also involved in the damage resistance, 29, 30 which resulted in damage survival and genomic instability.…”

Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy

“…No strong correlation between radiosensitivity and DNA-PKcs was found in a study of sporadic human ovarian cancer cell lines. The data suggested that DNA-PKcs copy number, expression level, or kinase activities are not reliable predictors of radiosensitivity in ovarian cancer ( 60 ). However, inhibition of DNA-PKcs has been shown by us to reverse cisplatin resistance in a panel of ovarian cancer cell lines ( 37 ).…”

Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma

“…Variations in DSB repair and differences in DNA-PKcs levels have been reported earlier in a radiosensitization study of ovarian cancer cell lines. (Langland et al, 2010). The cell line dependent variations in various enzyme expression levels could be a factor in the differences in the degree of DSB repair inhibition seen in this study.…”