Quercetin Promotes Apoptosis In Senescent Cells Induced By Ionizing Radiation

Cell senescence is a process in which cells irreversibly lose their ability to proliferate.Generally,cell senescence is considered to be a barrier that inhibits the development of cells with transformation tendency to tumor cells.However,there is growing evidence that senescent cells can trigger adverse effects in a variety of ways.Ionizing radiation leads to serious DNA damage in tumor cells.Severe DNA damage occurred in tumor cells especially after high-dose irradiation,which could not repair and continuous activation of DNA damage response signaling pathway and induce tumor cells to undergo senescence.Senescent tumor cells can undergo immune escape and survive,leaving the potential for tumor metastasis or recurrence.Currently,researchers have proposed a two-step strategy to induce tumor cell senescence through chemotherapy or radiotherapy and further induce apoptosis of senescent cells.Well known strategies for eliminating senescent cell effects include inducing senescent cells death by senolytics,reducing the effects of secretory phenotypes associated with senescence and remodeling the immune system to clear senescent cells.Quercetin is a small naturally molecule derived from food and a variety of plants.Recent studies have found that quercetin can inhibit proliferation and induce apoptosis of tumor cells.However,whether quercetin can kill senescent tumor cells,especially those induced by ionizing radiation,has not been reported so far.In this study,melanoma 92-1 and A375 cells were used,and the effect of quercetin on senescent melanoma cells after 10 Gy irradiation of X-rays and carbon ions was studied.The results are concluded as follows:(1)92-1 and A375 cells was induced senescence after 10 Gy irradiation of X-rays or carbon ions.After irradiation,the morphology of cells has becoming larger and flatter,and cells with un-repairing DNA damage in nucleus existed over a long period of time,cell cycle arrested for a long time and the activity of senescence-associated ?-galactosidase in cells increased significantly.All of these showed that 92-1 and A375 cells occurred senescence caused by ionizing radiation.(2)Quercetin could induce obvious apoptosis in senescent 92-1 cells induced by 10 Gy of ionizing irradiation,and the mechanism of inducing apoptosis is related to down-regulate expression of protein Cyclin D1 and survivin.Firstly,CCK8 cell proliferation detecting was used to determine the effect of quercetin on cell viability,and 50?M was selected as the optimal concentration.Then,quercetin treatment in 92-1 cells immediately after irradiation and in obviously senescent 92-1 cells after irradiation,could significantly induced the apoptotic morphology of the cells,and activation of the expression of apoptosis protein Cleaved Caspase-3 in cells to induce cell apoptosis.These indicate that quercetin can reduce the accumulation of senescent cells by inducing the apoptosis of cells,and decrease the survival proportion of the senescent cells after irradiation.In addition,the possible mechanism of quercetin in inducing apoptosis was discussed.We found that the cell cycle arrest in 92-1 cells treated with quercetin immediately after irradiation have changed,and quercetin treatment down-regulated the expression levels of protein Cyclin D1 and survivin in 92-1 senescent cells.In summary,melanoma 92-1 and A375 cells could be induced to senescence after 10 Gy irradiation of X-rays and carbon ions,and quercetin treatment can induce apoptosis of senescent cells,which has great potential in reducing adverse effects of senescence cancer cells induced by high dose of ionizing radiation.