DNA-PKcs inhibitor increases the sensitivity of gastric cancer cells to radiotherapy

摘要

Gastric cancer (GC) is a severe public health problem worldwide, particularly in China. Radiotherapy is the main locoregional treatment for various types of unresectable tumor, including GC. However, many patients fail to respond to radiotherapy due to the intrinsic radioresistance of cancer cells. This study was designed to investigate the effects and potential mechanism of radiosensitization associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor in human GC cell lines in vitro. Among the six GC cell lines (SGC7901, HGC-27, MKN45, MKN74, BGC823 and MGC803) that were exposed to increasing doses of IR (0, 2, 4, 6 and 8 Gy), the mean lethal dose and quasi-threshold dose measurements indicated that BGC823 and MGC803 were relatively insensitive to ionizing radiation (IR). IR induced significant elevation of gamma H2A histone family member X (gamma H2AX) in MKN45 cells compared with BGC823 cells. DNA-PKcs and phospho-DNA-PKcs protein levels were increased in BGC823 and MGC803 cells compared with other GC cell lines (SGC7901, HGC-27, MKN45 and MKN74). DNA-PKcs inhibition led to increased sensitivity of BGC823 and MGC803 cells to IR. NU7441 increased gamma H2AX expression in the nuclei of BGC823 cells following IR. Combination of DNA-PKcs and CK2 inhibition further increased the sensitivity of GC cells to IR. The combination of NU7441 and CX4945 increased gamma H2AX expression in the nucleus of BGC823 cells following IR compared with treatment with NU7441 alone. Taken together, the findings suggest that DNA-PKcs inhibitor increased the sensitivity of radioresistant BGC823 and MGC803 cells to radiotherapy through the cleaved-caspase3/gamma H2AX signaling pathway, thus presenting a potential treatment method for GC.