Preliminary investigation of glutamine transporter SLC7A8 role in mediating cuproptosis in patient-derived primary glioblastoma cell

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive glioma that is reported to exhibit elevated glutamine uptake and metabolism, termed as glutamine addiction, often associated with poor patient prognosis. Recently, a preliminary study identified glutamine transporter SLC7A8 to be highly upregulated in resistant GBM and associated with poor prognosis, with results intriguingly showing distinct responses between wild-type and resistant GBM upon SLC7A8 knockdown where increased viability was instead observed in the former. Cuproptosis is a recently discovered cell death mediated by the intracellular accumulation of copper ions upon elesclomol treatment. The current study aims to evaluate the role of SLC7A8 in patient-derived primary GBM cell line Pt#3 and explore its role in mediating cuproptosis through its effects towards cuproptosis markers, as well as other pathways. The current findings confirmed that SLC7A8 knockdown increased the viability of Pt#3 cells. Remarkably, its knockdown concurrently increased the cells’ sensitivity towards cuproptosis. While the exact mechanisms remain to be further elucidated, the results suggest that SLC7A8 indirectly mediate cuproptosis through promoting the TCA cycle and regulating intracellular copper transporters and chelators. SLC7A8 was also high associated with the immune responses in GBM in silico. Collectively, these findings suggests the prospects of inducing cuproptosis upon SLC7A8 knockdown as a novel therapeutic approach in GBM.