Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma

Version 1 : Received: 21 December 2022 / Approved: 23 December 2022 / Online: 23 December 2022 (04:10:22 CET)

A peer-reviewed article of this Preprint also exists.

Mansour, M.A.; Rahman, M.; Ayad, A.A.; Warrington, A.E.; Burns, T.C. P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma. Cancers 2023, 15, 1279. Mansour, M.A.; Rahman, M.; Ayad, A.A.; Warrington, A.E.; Burns, T.C. P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma. Cancers 2023, 15, 1279.

Abstract

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.

Keywords

P21; CDKN1A; glioblastoma; senescence; cancer senescence; gene overexpression; gene knock-in; CRISPR/Cas9; dCas; dCas-VPR

Subject

Medicine and Pharmacology, Oncology and Oncogenics

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