Targeting Therapy-Induced Senescence: The Role of p21 in Shifting Cellular Fate from Senescence to Apoptosis

Abstract ID 87494 Poster Board 045 Therapy-induced senescence (TIS) has become a matter of controversy among scientists over the last decade. There is an evidence that TIS is considered as a mode of cell death, while others see that the promotion of cellular aging during therapy is a stage through which the cell reprograms itself to become more aggressive. Therefore, the emergence of senolytics after exposure to chemotherapy or radiation has become an additional regiment by which we might shift the senescent cells to apoptosis. In this work, we investigated the role of p21, an essential driver for promoting senescence, when cells are exposed to DNA damaging agents such as doxorubicin. We hypothesize that interference with p21 suppresses doxorubicin-induced senescence and shift cancer cells to the fate of permanent cell death (apoptosis). We assessed the impact of doxorubicin treatment on senescence using β-galactosidase staining and apoptosis using TUNEL and Annexin V assays in p21^(+/+) and p21^(−/−) HCT116 cells. Both p21^(+/+) cells and p21^(−/−) cells were treated with doxorubicin to induce senescence. β-Galactosidase staining was remarkably observed in p21^(+/+) cells compared to p21^(−/−) cells. In addition, doxorubicin treatment significantly increased the senescent cell subpopulation in p21^(+/+) cells by 3.3-fold compared to untreated cells, while no significant increase in this treatment was observed in p21^(−/−) cells. These results indicate that p21^(+/+) cells significantly underwent senescence relative to p21^(−/−) cells upon doxorubicin exposure. Treatment with the chemotherapy agent noticeably increased DNA fragmentation in p21^(−/−) cells in comparison to p21^(+/+) cells. Apoptotic cell populations were significantly higher in doxorubicin-treated p21^(−/−) cells than in treated p21^(+/+) cells. Our data proved that functional p21 determines whether treated cells will undergo cellular senescence or apoptosis, indicating that p21 inhibition is a promising target of senolysis. Thus, development of p21 inhibitors might be a novel clinical approach to target therapy-induced senescent cells.