P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma

Simple Summary Current standard care for high-grade glioma involves maximal safe resection followed by chemoradiation. Recent studies showed that surviving cancer cells with an initially senescent phenotype following chemoradiation could escape senescence over time, giving rise to tumor cells that were more aggressive and resilient. Therefore, more powerful approaches are needed to either keep these glioma-initiating cells in a senescent state for longer or to eliminate these senescent cells prior to tumor recurrence. In this study, we demonstrate that P21 overexpression induces high levels of apoptosis in multiple human glioma cell lines and, in surviving cells, promotes cell cycle arrest and senescent gene expression. Additionally, we demonstrate that P21 overexpression induces senescence more rapidly and stably than the irradiation of human glioblastoma cells. Finally, we find that P21-overexpressing glioma cells selectively depend upon Bcl-xL to avoid apoptotic cell death. High-grade gliomas are the most common and aggressive adult primary brain tumors with a median survival of only 12-15 months. Current standard therapy consists of maximal safe surgical resection followed by DNA-damaging agents, such as irradiation and chemotherapy that can delay but not prevent inevitable recurrence. Some have interpreted glioma recurrence as evidence of glioma stem cells which persist in a relatively quiescent state after irradiation and chemotherapy, before the ultimate cell cycle re-entry and glioma recurrence. Conversely, latent cancer cells with a therapy-induced senescent phenotype have been shown to escape senescence, giving rise to more aggressive stem-like tumor cells than those present in the original tumor. Therefore, approaches are needed to either eliminate or keep these glioma initiating cells in a senescent state for a longer time to prolong survival. In our current study, we demonstrate that the radiation-induced cell cycle inhibitor P21 can provide a powerful route to induce cell death in short-term explants of PDXs derived from three molecularly diverse human gliomas. Additionally, cells not killed by P21 overexpression were maintained in a stable senescent state for longer than control cells. Collectively, these data suggest that P21 activation may provide an attractive therapeutic target to improve therapeutic outcomes.