P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma.
Moustafa A MansourMasum RahmanAhmad A AyadArthur E WarringtonTerry C BurnsPublished in: Cancers (2023)
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.
Keyphrases
- cell cycle
- cell cycle arrest
- cell death
- high grade
- induced apoptosis
- radiation induced
- cell proliferation
- endothelial cells
- stem cells
- free survival
- dna damage
- endoplasmic reticulum stress
- transcription factor
- pi k akt
- signaling pathway
- oxidative stress
- high glucose
- squamous cell carcinoma
- blood pressure
- type diabetes
- heart rate
- adipose tissue
- body composition
- stress induced
- cell free
- electronic health record
- diabetic rats