# Revealing the Roles of the SH3GLB1-Hydrogen Peroxide Axis in Glioblastoma Multiforme Cells

## TL;DR

This study explores how hydrogen peroxide and SH3GLB1 signaling affect glioblastoma cells and drug resistance.

## Contribution

The study reveals a novel role of the SH3GLB1-hydrogen peroxide axis in regulating glioblastoma cell responses and drug resistance.

## Key findings

- SOD2 regulates SH3GLB1 through hydrogen peroxide and AKT signaling.
- Combining TMZ with redox modulators reduces resistant tumor growth in animal models.
- HgCl2 reverses TMZ-induced SH3GLB1 expression via aquaporin-9/AKT signaling.

## Abstract

Glioblastoma (GBM) is a prevalent malignant brain tumor prone to drug resistance. We previously found a strong correlation between SH3 domain GRB2-like endophilin B1 (SH3GLB1) and superoxide dismutase 2 (SOD2), which converts O2 to hydrogen peroxide (H2O2). Prior studies show that H2O2 redox signaling is vital for physiological processes and can drive tumor progression. Therefore, we aim to define how H2O2 signaling regulates SH3GLB1 and AKT (protein kinase B) pathways in GBM and to assess whether modulating H2O2 reverses temozolomide (TMZ) resistance.

We used cultured cells and pharmacological inhibitors and activators to confirm the significance of H2O2 signaling. GBM cells were used to verify the role of H2O2 signaling in cell state transitions and animal experiments identified optimal treatment strategies.

We found that SOD2 acts as an upstream regulator of SH3GLB1. When SOD inhibitors and TMZ were combined, cells showed reduced SH3GLB1 and autophagy levels. SH3GLB1 was found to be regulated by H2O2 via AKT signaling using redox homeostasis-regulating experiments. Although treatment-induced changes in mitochondrial H2O2 levels mirrored those in the cytosol, parental and resistant cells exhibited divergent fates, highlighting cell-fate plasticity. TMZ combined with a redox modulator reduced resistant tumor cell growth (about 2/3 reduction of tumor size; p < 0.05) and suppressed SH3GLB1 and autophagy levels in animal models. The TMZ-induced increase in SH3GLB1 expression was reversed by HgCl2, which inhibited the aquaporin-9/AKT signaling.

Overall, these findings underscore the importance of H2O2-SH3GLB1 signaling in GBM and may inform future therapeutic strategies for overcoming TMZ resistance.