TMIC-73. Quercetin-Induced Membrane-TRAIL Release Promotes Apoptosis in Glioblastoma

Abstract Glioblastoma IDH wild-type (GBM) is a highly aggressive type of brain cancer with a dismal prognosis and limited treatment options. Our aim was to explore a natural course of treatment for GBM. We assessed the ability of the flavonoid quercetin to induce apoptosis in combination with recombinant human soluble tumor necrosis factor-related apoptosis inducing ligand (rhTRAIL) in various GBM cell lines (M059K, T98G, A172) and non-transformed astrocytes using western blotting, confocal microscopy, and flow cytometry. Healthy astrocytes are typically resistant to TRAIL-induced apoptosis due to low surface expression of death receptor 5 (DR5). As expected, quercetin alone did not induce significant apoptosis in normal astrocytes, however, rhTRAIL alone did result in a minimal amount of apoptosis in a population of normal astrocytes with elevated levels of surface DR5. In contrast to astrocytes, quercetin alone induced apoptosis through both the intrinsic and extrinsic pathways in all GBM cell lines, albeit with different sensitivities. M059K were the most responsive, followed by T98G and A172. This led to the novel observation that GBM cells possess endogenous membrane-TRAIL (mTRAIL), and that quercetin increases mTRAIL trafficking to the cell surface in a time- and concentration-dependent manner. In all GBM cells, cotreatment with quercetin and rhTRAIL was more effective in inducing apoptosis than either treatment alone. M059K were relatively resistant to rhTRAIL compared to T98G and A172, despite similar surface DR5 expression levels. Thus, we found that quercetin, in vitro, can induce apoptosis in GBM cells by promoting trafficking of endogenous mTRAIL to the cancer cell surface, which can then interact with DR5 on cancer cells in a paracrine or autocrine manner, destroying the tumor cells. This novel mechanism of GBM self-destruction in the presence of quercetin, combined with quercetin’s reported ability to cross the blood-brain barrier, highlights its potential as a promising therapeutic for GBM.