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Quercetin Increases Expression of Membrane-TRAIL in Glioblastoma Cells Resulting in Apoptosis
by
Erin M. Thorpe
1,2, 
Gaëlle Muller-Greven
3,
Jamila Hirbawi
1,
Candece L. Gladson
3,4 and
Michael Kalafatis
1,2,* 1
Department of Chemistry, Cleveland State University, Science and Research Center, Cleveland, OH 44115, USA
2
Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, OH 44115, USA
3
Department of Cancer Science, Cleveland Clinic, Cleveland, OH 44195, USA
4
Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH 44195, USA
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(19), 3197; https://doi.org/10.3390/cancers17193197
Submission received: 18 August 2025
/
Revised: 25 September 2025
/
Accepted: 27 September 2025
/
Published: 30 September 2025
(This article belongs to the Collection Innovations in Cancer Drug Development Research)
Simple Summary
Glioblastoma (GBM) is a highly aggressive type of brain cancer with limited treatment options and typically a terminal prognosis. The immune system possesses a protein that is called tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that naturally can destroy cancer cells. Because our aim was to explore a natural course of treatment for GBM, we assessed the ability of the natural compound quercetin to induce cell death in various GBM cell lines and non-cancerous normal brain cells. In the absence of added TRAIL, quercetin did not induce cell death in normal brain cells, but quercetin alone induced cell death in all GBM cell lines, in a TRAIL-dependent manner. This led to the novel observation that GBM cells already have TRAIL inside them. We further demonstrated that quercetin increases TRAIL trafficking from inside the cell to its surface, resulting in the destruction of the neighboring cancer cells. Thus, hypothetically, in the presence of quercetin, an entire brain tumor could be treated without any harmful effects on bordering normal brain cells. This novel and unexpected mechanism of GBM self-destruction in the presence of quercetin, combined with quercetin’s inability to harm normal brain cells, highlights its potential as a promising therapeutic for GBM.
Abstract
Background/Objectives: Glioblastoma isocitrate dehydrogenase (IDH)-wild type (GBM) belongs to a deadly class of cancers with a limited number of effective therapies and a dismal prognosis. Quercetin is a natural flavonoid with proven anti-cancer effects. This study aimed to assess the effect of quercetin on recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL)-mediated apoptosis in various GBM cells and control astrocytes. Methods: Two astrocyte cell lines and three GBM cell lines, M059K, T98G, and A172, were treated with quercetin (±rhTRAIL), and the results were evaluated by Western blotting, confocal microscopy, and flow cytometry analyses. Results: Quercetin alone did not induce apoptosis in normal astrocytes. Surprisingly, quercetin alone induced apoptosis in all GBM cell lines through both the intrinsic and extrinsic pathways of apoptosis in a TRAIL-dependent manner. M059K were the most sensitive to quercetin-induced apoptosis, followed by T98G and A172. We determined that GBM cells possess endogenous membrane-TRAIL, and that quercetin, in a time- and concentration-dependent manner, increased the trafficking of membrane-TRAIL to the cell surface. Conclusions: We demonstrate that quercetin alone induces apoptosis in GBM cell lines by facilitating endogenous membrane-TRAIL trafficking to the cell surface, where it can interact with death receptors already present on the surface of neighboring cancer cells, resulting in cell death. This unexpected finding may prove to be invaluable for potential future treatment of patients with GBM, since administration of quercetin can cause increased trafficking of membrane-TRAIL to the cell surface, inducing cancer cell apoptosis without affecting neighboring normal cells.
