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Positron Emission Tomography-based Dose Painting Radiation Therapy in a Glioblastoma Rat Model using the Small Animal Radiation Research Platform
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PERK Regulates Glioblastoma Sensitivity to ER Stress Although Promoting Radiation Resistance

David Y A Dadey1,2,3, Vaishali Kapoor1, Arpine Khudanyan1,4

  • 1Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.

Molecular Cancer Research : MCR
|July 12, 2018
PubMed

Insights

Glioblastoma multiforme (GBM) survival can be improved by targeting the PERK pathway. Ionizing radiation activates this pathway, which has dual roles in cell survival and death, offering new therapeutic strategies for GBM patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
  • Therapeutic resistance in GBM necessitates understanding its molecular mechanisms.
  • The protein kinase R-like endoplasmic reticulum kinase (PERK) pathway regulates endoplasmic reticulum (ER) stress response.

Purpose of the Study:

  • Investigate the role of the PERK-eIF2α-ATF4 pathway in GBM following ionizing radiation (IR).
  • Determine how IR affects PERK pathway activation in GBM cells.
  • Explore the therapeutic potential of modulating this pathway in GBM treatment.

Main Methods:

  • Studied PERK-eIF2α-ATF4 pathway activation in GBM after IR.
  • Utilized PERK inhibition to assess its role in IR-induced signaling.
  • Employed Sal003, a phospho-eIF2α phosphatase inhibitor, to modulate PERK signaling.

Main Results:

  • Ionizing radiation (IR) activates the PERK pathway, leading to eIF2α phosphorylation.
  • IR enhances the pro-death function of PERK signaling when combined with Sal003.
  • ATF4 acts as a mediator of prosurvival signaling during the radiation response.

Conclusions:

  • Radiation-induced ER stress signaling contributes to adaptive survival mechanisms in GBM during radiotherapy.
  • The PERK/eIF2α/ATF4 axis plays a role in modulating cell viability in irradiated GBM.
  • Targeting the dual function of PERK may enhance radiation therapy efficacy for GBM.

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