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.
背景/目的：胶质母细胞瘤异柠檬酸脱氢酶（IDH）野生型（GBM）属于一类致死性癌症，其有效治疗方法有限且预后不良。槲皮素是一种天然黄酮类化合物，已被证实具有抗癌作用。本研究旨在评估槲皮素对重组人肿瘤坏死因子相关凋亡诱导配体（rhTRAIL）介导的多种GBM细胞及对照星形胶质细胞凋亡的影响。方法：对两种星形胶质细胞系及三种GBM细胞系（M059K、T98G和A172）进行槲皮素（±rhTRAIL）处理，并通过蛋白质印迹、共聚焦显微镜和流式细胞术分析评估结果。结果：单独使用槲皮素未诱导正常星形胶质细胞凋亡。令人惊讶的是，单独使用槲皮素通过TRAIL依赖的方式，同时激活内在和外在凋亡通路，在所有GBM细胞系中诱导了凋亡。M059K细胞对槲皮素诱导的凋亡最为敏感，其次是T98G和A172细胞。我们确定GBM细胞具有内源性膜结合TRAIL，且槲皮素以时间和浓度依赖的方式促进了膜结合TRAIL向细胞表面的转运。结论：本研究表明，槲皮素通过促进内源性膜结合TRAIL向细胞表面转运，使其与邻近癌细胞表面已存在的死亡受体相互作用，从而诱导GBM细胞系发生凋亡。这一意外发现可能对未来GBM患者的潜在治疗具有重要价值，因为槲皮素的给药可增加膜结合TRAIL向细胞表面的转运，在不影响邻近正常细胞的情况下诱导癌细胞凋亡。
Quercetin Increases Expression of Membrane-TRAIL in Glioblastoma Cells Resulting in Apoptosis
肿瘤(癌症)患者之家