Related Experiment Video
Updated: Jun 28, 2025
Glioblastoma Relapse Post-Resection Model for Therapeutic Hydrogel Investigations
Published on: February 24, 2023
Endoplasmic Reticulum Stress in Gliomas: Exploiting a Dual-Effect Dysfunction through Chemical Pharmaceutical
Daniel García-López1,2, Montserrat Zaragoza-Ojeda1, Pilar Eguía-Aguilar1,3
1Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico.
Abstract:
The endoplasmic reticulum maintains proteostasis, which can be disrupted by oxidative stress, nutrient deprivation, hypoxia, lack of ATP, and toxicity caused by xenobiotic compounds, all of which can result in the accumulation of misfolded proteins. These stressors activate the unfolded protein response (UPR), which aims to restore proteostasis and avoid cell death. However, endoplasmic response-associated degradation (ERAD) is sometimes triggered to degrade the misfolded and unassembled proteins instead. If stress persists, cells activate three sensors: PERK, IRE-1, and ATF6. Glioma cells can use these sensors to remain unresponsive to chemotherapeutic treatments. In such cases, the activation of ATF4 via PERK and some proteins via IRE-1 can promote several types of cell death. The search for new antitumor compounds that can successfully and directly induce an endoplasmic reticulum stress response ranges from ligands to oxygen-dependent metabolic pathways in the cell capable of activating cell death pathways. Herein, we discuss the importance of the ER stress mechanism in glioma and likely therapeutic targets within the UPR pathway, as well as chemicals, pharmaceutical compounds, and natural derivatives of potential use against gliomas.
Insights
Endoplasmic reticulum stress, triggered by various factors, can lead to glioma cell survival or death. Targeting the unfolded protein response (UPR) pathway offers potential new strategies for glioma treatment.
Area of Science:
- Cellular Biology
- Oncology
- Biochemistry
Background:
- The endoplasmic reticulum (ER) is crucial for maintaining cellular protein homeostasis (proteostasis).
- ER proteostasis can be disrupted by oxidative stress, nutrient deprivation, hypoxia, ATP depletion, and xenobiotic toxicity, leading to misfolded protein accumulation.
- The unfolded protein response (UPR) is activated to restore proteostasis, but persistent stress can trigger cell death pathways.
Purpose of the Study:
- To discuss the significance of ER stress mechanisms in glioma.
- To identify potential therapeutic targets within the UPR pathway for glioma treatment.
- To explore chemical, pharmaceutical, and natural compounds that induce ER stress in glioma cells.
Main Methods:
- Review of literature on ER stress, UPR, and glioma.
- Analysis of UPR sensor activation (PERK, IRE-1, ATF6) in glioma cells.
- Identification of compounds that induce ER stress and cell death.
Main Results:
- Glioma cells can evade chemotherapy by manipulating UPR sensors.
- Activation of PERK and IRE-1 pathways can lead to glioma cell death.
- ER stress induction is a promising strategy for developing novel glioma therapeutics.
Conclusions:
- The ER stress pathway is a critical factor in glioma biology and therapeutic resistance.
- Targeting UPR sensors and related pathways presents a viable strategy for novel anti-glioma drug development.
- Investigating compounds that induce ER stress holds potential for new glioma treatments.
