PERK regulates glioblastoma sensitivity to ER stress although promoting radiation resistance

David Y.A. Dadey, Vaishali Kapoor, Arpine Khudanyan, Dinesh Thotala and Dennis E. Hallahan. Molecular Cancer Research, Volume 16, Issue 10, October 2018, Pages 1447-1453 Read More

Abstract

The aggressive nature and inherent therapeutic resistance of glioblastoma multiforme (GBM) has rendered the median survival of afflicted patients to 14 months. Therefore, it is imperative to understand the molecular biology of GBM to provide new treatment options to overcome this disease. It has been demonstrated that the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is an important regulator of the endoplasmic reticulum (ER) stress response. PERK signaling has been observed in other model systems after radiation; however, less is known in the context of GBM, which is frequently treated with radiation-based therapies. To investigate the significance of PERK, we studied activation of the PERK- eIF2α-ATF4 pathway inGBMafter ionizing radiation (IR). By inhibiting PERK, it was determined that ionizing radiation (IR)-induced PERK activity led to eIF2a phosphorylation. IR enhanced the prodeath component of PERK signaling in cells treated with Sal003, an inhibitor of phospho-eIF2α phosphatase. Mechanistically, ATF4 mediated the prosurvival activity during the radiation response. The data support the notion that induction of ER stress signaling by radiation contributes to adaptive survival mechanisms during radiotherapy. The data also support a potential role for the PERK/eIF2α/ATF4 axis in modulating cell viability in irradiated GBM. Implications: The dual function of PERK as a mediator of survival and death may be exploited to enhance the efficacy of radiation therapy. © 2018 American Association for Cancer Research.

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Posted on October 31, 2018
Posted in: HPAN, Neurodegeneration, Publications Authors: