br The major regulator of radiation sensitivity Tumor cell r

The major regulator of radiation sensitivity Tumor cell resistance to radiation is a big issue for radiation therapy, and a major concern of radiation oncologist. Understanding the regulation mechanism of radiation sensitivity is still a research hotspot. Increased sensitivity to ionizing radiation (IR) has been shown to be due to defects in DNA double-strand break repair machinery [65]. Previous studies have demonstrated that DNA-PKcs−/− mice are hypersensitive to DNA damage induced by genotoxic stress such as radiation, and undergo Atm- and p53-dependent apoptosis [66], [67], [68]. In response to radiation, the DNA-PK/AKT/GSK3b-mediated cyclin D1 overexpression results in an acquired radioresistance in human tumor cytokine receptor HepG2 and HeLa [69]. The radiation-induced cyclin D1 overexpression leads to the forced progression of S-phase with the induction of DNA double strand breaks. This DNA damage activates DNA-PK, which in turn activated AKT and inactivated GSK3b, thus completing a positive feedback loop of cyclin D1 overproduction. Moreover, the DNA damage also activates other DNA repair pathway, including ataxia telangiectasia mutated (ATM)- and Chk1-dependent DNA damage checkpoint and homologous recombination repair, which may explain why long-term fractionated radiation-treated cells repair DNA damage faster than non-FR-treated cells. DNA-PK or DSB repair inhibition increases the sensitivity of tumor cells to radiation. For example, inhibition of the AKT/GSK3b/cyclin D1/Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance [69]. Zhou laboratory [70] have shown that the overexpression of the anti-DPK3-scFv (the single-chain variable antibody fragments) resulted in decrease of the kinase activity of DNA-PK and DSB repair capability. The lengths of comet tail were persisted and γ-H2AX foci were reduced in the anti-DPK3-scFv transfected cells, and the radiation-induced Ser 473 phosphorylation of its target Akt and Ser 2056 phosphorylation of DNA-PKcs were decreased too. The growth rate and apoptosis data have also demonstrated that the anti-DPK3-scFv enhanced the sensitivity of tumours transplanted in Balb/c athymic mice to radiation therapy. Moreover, a chemical compound of PI3k kinase inhibitor, LY294002 significantly radiosensitized cervical cancer HeLa cells when administered for just 12h following radiation [71]. Compared to the control, cell growth curves were decreased with brief LY294002 treatment at a dose only inhibiting DNA-PK activity, but not ATM or ATR. The radiation-induced phosphorylation of H2AX was significantly elevated in cells treated with LY294002. The Rodemann research group demonstrates that the selective cyclooxygenase (COX)-2 inhibitor, celecoxib-enhanced radiation sensitivity is dependent on DNA-PK activity, but not COX-2 activity [72]. The celecoxib inhibits basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR) in A549, HSF7, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization [72]. The inhibition of EGFR nuclear transportation abolished radiation-induced DNA-PK activation [72], [73]. These observations suggest that the importance of the DNA-PK catalytic subunit (DNA-PKcs) for the modulation of cellular radiosensitivity by celecoxib. The Saha group also demonstrates that DNA-PKcs modulates the celecoxib-induced cellular radiosensitivity [74].