ABSTRACT
Resveratrol (RSV) has broad prospective applications as a radiation protection drug, but its mechanism of action is not yet clear. Here, we found that 5 µM RSV can effectively reduce the cell death caused by irradiation. Irradiation leads to G2/M phase arrest in the cell cycle, whereas RSV treatment increases S-phase cell cycle arrest, which is associated with sirtuin 1 (SIRT1) regulation. Meanwhile, RSV promotes DNA damage repair, mainly by accelerating the efficiency of homologous recombination repair. Under oxidative stress, tyrosyl-tRNA synthetase (TyrRS) is transported to the nucleus to protect against DNA damage. RSV can promote TyrRS acetylation, thus promoting TyrRS to enter the nucleus, where it regulates the relevant signaling proteins and reduces apoptosis and DNA damage. SIRT1 is a deacetylase, and SIRT1 knockdown or inhibition can increase TyrRS acetylation levels, further reducing radiation-induced apoptosis after RSV treatment. Our study revealed a new radiation protection mechanism for RSV, in which the acetylation of TyrRS and its translocation into the nucleus is promoted, and this mechanism may also represent a novel protective target against irradiation.-Gao, P., Li, N., Ji, K., Wang, Y., Xu, C., Liu, Y., Wang, Q., Wang, J., He, N., Sun, Z., Du, L., Liu, Q. Resveratrol targets TyrRS acetylation to protect against radiation-induced damage.
Subject(s)
Apoptosis , G2 Phase Cell Cycle Checkpoints , Radiation Injuries, Experimental , Resveratrol/pharmacology , Signal Transduction , Tyrosine-tRNA Ligase , Animals , Apoptosis/drug effects , Apoptosis/genetics , Apoptosis/radiation effects , DNA Damage , DNA Repair/drug effects , DNA Repair/genetics , DNA Repair/radiation effects , G2 Phase Cell Cycle Checkpoints/drug effects , G2 Phase Cell Cycle Checkpoints/genetics , G2 Phase Cell Cycle Checkpoints/radiation effects , HEK293 Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , M Phase Cell Cycle Checkpoints/genetics , M Phase Cell Cycle Checkpoints/radiation effects , Radiation Injuries, Experimental/genetics , Radiation Injuries, Experimental/metabolism , Radiation Injuries, Experimental/pathology , Radiation Injuries, Experimental/prevention & control , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/radiation effects , Sirtuin 1/genetics , Sirtuin 1/metabolism , Tyrosine-tRNA Ligase/genetics , Tyrosine-tRNA Ligase/metabolismABSTRACT
Radiotherapy resistance in patient with nonsmall cell lung cancer (NSCLC) reduces patient survival and remains a significant challenge for the treatment of NSCLC. Radiation resistance has been demonstrated to be affected by secreted factors, yet it remains unclear how autocrine secretions affect the radioresistance of NSCLC cells. In the present study, the NSCLC cell line, NCIH460, was irradiated with γrays (4 Gy) and then cultured in medium from H460 cells or normal medium to examine the potential influence of cell secretions on the radiation resistance of H460 cells. Cell viability, accumulation of reactive oxygen species and DNA repair capacity were all markedly improved in the irradiated H460 cells that were cultured in conditioned medium (CM), compared with those cells cultured in normal medium. In addition, G2/M cell cycle arrest and upregulation of homologous recombination repair proteins were observed in the CMtreated cells, while exosomes secreted by H460 cells had no influence on the radiation resistance of H460 cells. Taken together, these results indicate that autocrine secretions enhance the radiation resistance of γirradiated H460 cells and that these secretions mainly affect the DNA repair process.
