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  • 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 AZD6482 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].
    The involvement of DNA-PK in the inflammatory response Protein complex, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) regulates many genes involved in mammalian immune and inflammatory responses, apoptosis, cell proliferation, and differentiation in response to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens [75], [76], [77]. Activated NF-κB unmasks the nuclear translocation and binding of NF-κB to specific κB consensus sequences in the chromatin as well as the activation of specific subsets of genes. Moreover, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. For example, expression of VCAM-1 is critical for the initiation and progression of inflammatory diseases, such as asthma and arthrosclerosis [78], [79], as well as cancer [80]. The expression of VCAM-1 and other adhesion molecules plays an important role in both the recruitment of Th2 cells and the accumulation of eosinophils in allergic inflammatory foci [81].