Concurrent Ferroptosis and Apoptosis in Resveratrol-Treated Glioblastoma Cells: Relevance With NRF2 Downregulation and Oxidative Stress

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Glioblastomas (GBMs) are aggressive brain tumors with poor prognosis.
• Resveratrol (RES) shows potential in GBM treatment by inducing cell death.
• The precise mechanisms of RES-induced cell death and the role of NFE2-related factor 2 (NRF2) signaling are not fully understood.

Purpose of the Study:

• To investigate the cell death patterns induced by RES in GBM cells.
• To elucidate the role of NRF2 signaling in GBM cell response to RES.
• To evaluate the therapeutic potential of RES in an in vivo GBM model.

Main Methods:

• Utilized RES-sensitive (U251) and less-sensitive (LN428) GBM cell lines.
• Performed in silico analysis of NRF2 expression in GBM using TCGA dataset.
• Administered RES in vitro and in vivo (orthotopic GBM xenograft rat model).
• Assessed cell viability, NRF2 levels, ROS, Fe2+, lipid peroxidation, apoptosis, and ferroptosis markers (xCT, GPX4, HO-1).
• Used Ferrostatin-1 and Z-VAD FMK inhibitors to confirm cell death pathways.

Main Results:

• High NRF2 expression correlates with GBM progression.
• RES treatment decreased NRF2 levels in U251 cells, leading to suppressed growth.
• RES induced ferroptosis (elevated Fe2+, ROS, lipid peroxidation) and apoptosis in U251 cells.
• NRF2-regulated ferroptosis markers (xCT, GPX4) were downregulated by RES in sensitive cells.
• Combined ferroptosis and apoptosis inhibition rescued U251 cells.
• In vivo RES administration induced both ferroptosis and apoptosis in GBM xenografts.

Conclusions:

• RES induces a dual cell death mechanism (ferroptosis and apoptosis) in sensitive GBM cells.
• NRF2 signaling status is a critical determinant of GBM cell sensitivity to RES.
• Targeting NRF2 pathways may enhance resveratrol's efficacy against glioblastomas.