34 Therapeutic Targeting of the SLC7A11-GCLM-GPX4 Axis Sensitizes Glioblastoma to Ferroptosis and Associates with Poor Survival

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumor with a dismal prognosis. The high proliferative activity of GBM is prone to generating oxidative stress, which must be counteracted to support cell survival and prevent ferroptotic cell death. The present study evaluated the expression of the GPX-4 and GCLM involved in redox homeostasis in GBM and their possible implications for tumor biology, clinical outcome, and therapeutic potential. The mRNA and protein expression were assessed by qPCR and immunohistochemistry, respectively, in 85 GBMs. For comparison, astrocytomas, grade 4 (n = 19), grade 2/3 (IDH-mutant) (n = 15), and oligodendrogliomas, grade 2/3 (IDH-mutant) (n = 13), were also evaluated. Normal brain (n = 5) used as control. In vitro analysis was performed on the U87MG and LN229 glioma cell lines. MTT assay, migration/invasion assay, and flow-cytometric assay (for cell death) were performed. The expression of GPX-4 and GCLM was significantly higher in GBM than in normal brain and lower-grade gliomas at mRNA and protein levels. High GPX4 expression was associated with significantly higher MIB-1 labeling. Inhibition of GPX-4/GCLM in vitro by RSL-3, FIN-56, and BSO was associated with increased cell death, elevated lipid ROS and reduced invasion and migration. Strong expression of GPX-4 and GCLM was associated with shorter overall survival in gliomas and GBM together. The GPX4/GCLM axis, which balances redox, is highly expressed and crucial for GBM cell survival and aggressive biological behavior. Given its predominantly immunopositivity in neoplastic cells and strong positivity in GBM, it may be a valuable adjunct to diagnosis. The present study also emphasized the role of GPX-4/GCLM as a potential therapeutic target, as demonstrated by RSL3, FIN56, and BSO.