Research On The Role Of Radiation-induced Tumor Cell Apoptosis Or Senescence In Tumor Cell Repopulation

Purpose:Radiotherapy is an effective cancer treatment.However,tumor cells following radiation treatment are postulated to generate potent growth signals to stimulate the repopulation of adjacent surviving tumor cells,which may promote tumor recurrence.Tumor repopulation is yet an understudied phenomenon,partly due to the negligence of the molecular mechanisms.In this study,we explored the role of apoptosis and senescence in tumor repopulation.Methods:Western blotting,quantitative real-time PCR,enzyme-linked immunosorbent assay,luciferase reporter assay and SA-β-Gal assay were used to identify the possible molecules and pathways in tumor repopulation after radiotherapy in vitro.Finally,xenograft tumor assays was used to confirm the mechanism in vivo.Results:1.We found that radiation induced DNA damage response（DDR）and Caspase-3activation,as well as promoted tumor repopulation in cancer cells.Unexpectedly,depleting caspase-3 significantly attenuated ataxia-telangiectasia mutated kinase（ATM）/p53-mediated DDR via attenuating endonuclease G（Endo G）nuclear migration,thus decreasing the growth-promoting effect of irradiated dying cells.Moreover,we identified p53 as a regulator of the Cox-2/PGE₂ axis,which was probably involved in Caspase-3-centered tumor repopulation after radiotherapy.Additionally,depleting Caspase-3 in NSCLC cells showed impaired tumor growth in nude mice model.2.Radiation induced tumor cell senescence as well as promoted tumor repopulation;senescence inhibitors Rapamycin and Torin1 could inhibit tumor repopulation after radiation;radiation-induced senescent cancer cells might secret LCN2 factor;Using LCN2 neutralizing antibody attenuated tumor repopulation;LCN2 factor could stimulate proliferation of tumor cells.Conclusions:Our findings demonstrated that 1.Caspase-3 was implicated in tumor repopulation and that was accompanied by promoting DDR and downstream ATM/p53/Cox-2/PGE₂ axis activation in cancer cells;2.radiation-induced senescenct tumor cells could release LCN2,which promoted tumor repopulation.These hitherto undescribed signaling pathways may deepen insight into the radiobiology and provide therapeutic targets to reduce cancer recurrence after radiotherapy.