Heterogeneous expression and cancer-selective regulation of endogenous membrane TRAIL by quercetin across various human cancer cell lines

We have recently shown that several human glioblastoma cell lines (M059K, T98G, A172), as well as normal human astrocytes, possess endogenous tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In addition, we demonstrated that the flavonoid quercetin promotes the trafficking of endogenous membrane TRAIL (mTRAIL) to the plasma membrane in glioblastoma cells, where it can interact with death receptors already present on the surface of neighboring cancer cells and trigger apoptosis through both the extrinsic and intrinsic pathways. In contrast, although normal human astrocytes also express endogenous mTRAIL, quercetin treatment did not enhance its trafficking to the plasma membrane or induce apoptosis. Together, these observations suggest that quercetin selectively activates mTRAIL-mediated apoptosis in cancer cells but not in normal cells ( Thorpe et al., Cancers 2025, 17, 3197; https://doi.org/10.3390/cancers17193197). The present study explores whether mTRAIL expression and responsiveness to quercetin extend across a broader spectrum of human cancer and non-malignant cell lines. Western blotting and flow cytometry were used to evaluate mTRAIL expression in a panel of human cancer and normal cell lines, including breast cancer (MCF-7, BT-20, HCC1937), melanoma (A375, MeWo, WM164), Burkitt lymphoma (RA-1, DG-75, Daudi), normal fibroblasts (08398), and additional models currently under investigation. Endogenous mTRAIL was detected in several malignant and non-malignant lines, including MCF-7, HCC1937, A375, RA-1, Daudi, and 08398 fibroblasts, but was absent in BT-20, MeWo, WM164, and DG-75. In RA-1 and A375 cancer cells, flow cytometry further confirmed that quercetin treatment increased cell-surface mTRAIL in a concentration-dependent manner, resulting in apoptosis. Collectively, including data from our previously published findings, endogenous mTRAIL expression was detected in 8 of 12 human cancer cell lines (67%) and in all 3 non-transformed cell lines (100%), indicating that expression may vary among cancer cell lines but appears to be consistent in normal cells. Overall, these findings support a role for quercetin in promoting mTRAIL trafficking and presentation at the plasma membrane, ultimately resulting in the demise of neighboring cancer cells. Ongoing studies aim to elucidate the functional significance of endogenous mTRAIL expression across various cell types and to define the molecular mechanism by which quercetin promotes mTRAIL trafficking to the plasma membrane of malignant but not normal cells, with the goal of establishing its potential therapeutic relevance across different cancer types.