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Published on: April 24, 2021
Targeting of endoplasmic reticulum (ER) stress in gliomas
Mariam Markouli1, Dimitrios Strepkos1, Athanasios G Papavassiliou1
1Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Abstract:
Gliomas remain a group of malignant brain tumors with dismal prognosis and limited treatment options with molecular mechanisms being constantly investigated. The past decade, extracellular stress and intracellular DNA damage have been shown to disturb proteostasis leading to Endoplasmic Reticulum (ER) stress that is implicated in the regulation of gene expression and the pathogenesis of several tumor types, including gliomas. Upon ER stress induction, neoplastic cells activate the adaptive mechanism of unfolded protein response (UPR), an integrated signaling system that either restores ER homeostasis or induces cell apoptosis. Recently, the manipulation of the UPR has emerged as a new therapeutic target in glioma treatment. General UPR activators or selective GRP78, ATF6 and PERK inducers have been detected to modulate cell proliferation and induce apoptosis of glioma cells. At the same time, target-specific UPR inhibitors and small molecule proteostasis disruptors, work in reverse to increase misfolded proteins and cause a dysregulation in protein maturation and sorting, thus preventing the growth of neoplastic cells. Herein, we discuss the pathogenic implication of ER stress in gliomas onset and progression, providing an update on the current UPR modifying agents that can be potentially used in glioma treatment.
Insights
Endoplasmic Reticulum (ER) stress and the unfolded protein response (UPR) play key roles in glioma development. Modulating the UPR offers a promising new therapeutic strategy for treating these aggressive brain tumors.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cellular Stress Response
Background:
- Gliomas are aggressive brain tumors with poor outcomes and limited therapeutic options.
- Endoplasmic Reticulum (ER) stress, triggered by extracellular and intracellular damage, disrupts proteostasis and influences gene expression in tumors, including gliomas.
- The unfolded protein response (UPR) is a cellular mechanism that responds to ER stress, either promoting cell survival or inducing apoptosis.
Purpose of the Study:
- To discuss the role of ER stress in glioma pathogenesis and progression.
- To review current therapeutic strategies targeting the UPR in glioma treatment.
Main Methods:
- Literature review of studies investigating ER stress and UPR in gliomas.
- Analysis of therapeutic agents that modulate UPR pathways.
Main Results:
- ER stress is implicated in the initiation and advancement of gliomas.
- Both UPR activators (e.g., GRP78, ATF6, PERK inducers) and inhibitors (e.g., small molecule proteostasis disruptors) show potential in modulating glioma cell proliferation and inducing apoptosis.
- Targeting UPR pathways can disrupt protein maturation and sorting, inhibiting neoplastic cell growth.
Conclusions:
- The UPR represents a significant therapeutic target for glioma treatment.
- Manipulating UPR pathways, through activators or inhibitors, offers novel strategies to combat glioma progression and induce tumor cell death.
