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Updated: Jul 11, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Enhanced Sensitivity to ALDH1A3-Dependent Ferroptosis in TMZ-Resistant Glioblastoma Cells
Yang Wu1, Sophie Franzmeier1,2, Friederike Liesche-Starnecker3
1Department of Neuropathology, Institute of Pathology, School of Medicine, Technical University Munich, 81675 Munich, Germany.
Abstract:
Temozolomide (TMZ) is standard treatment for glioblastoma (GBM); nonetheless, resistance and tumor recurrence are still major problems. In addition to its association with recurrent GBM and TMZ resistance, ALDH1A3 has a role in autophagy-dependent ferroptosis activation. In this study, we treated TMZ-resistant LN229 human GBM cells with the ferroptosis inducer RSL3. Remarkably, TMZ-resistant LN229 clones were also resistant to ferroptosis induction, although lipid peroxidation was induced by RSL3. By using Western blotting, we were able to determine that ALDH1A3 was down-regulated in TMZ-resistant LN229 cells. Most intriguingly, the cell viability results showed that only those clones that up-regulated ALDH1A3 after TMZ withdrawal became re-sensitized to ferroptosis induction. The recovery of ALDH1A3 expression appeared to be regulated by EGFR-dependent PI3K pathway activation since Akt was activated only in ALDH1A3 high clones. Blocking the EGFR signaling pathway with the EGFR inhibitor AG1498 decreased the expression of ALDH1A3. These findings shed light on the potential application of RSL3 in the treatment of glioblastoma relapse.
Insights
Temozolomide resistance in glioblastoma is linked to ALDH1A3. Upregulating ALDH1A3 re-sensitizes resistant cells to ferroptosis, offering a potential treatment strategy for glioblastoma relapse.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Cell Death Mechanisms
Background:
- Temozolomide (TMZ) is a standard glioblastoma (GBM) treatment, but resistance and recurrence remain significant challenges.
- Aldehyde dehydrogenase 1A3 (ALDH1A3) is implicated in GBM recurrence and TMZ resistance, and also influences ferroptosis.
- Ferroptosis, a regulated cell death pathway, is a potential therapeutic target in cancer.
Purpose of the Study:
- To investigate the role of ALDH1A3 in temozolomide-resistant glioblastoma cells and their sensitivity to ferroptosis.
- To explore the mechanisms underlying ALDH1A3 regulation and its impact on glioblastoma cell viability.
Main Methods:
- Treatment of TMZ-resistant LN229 human GBM cells with the ferroptosis inducer RSL3.
- Western blotting to assess ALDH1A3 and Akt protein levels.
- Cell viability assays to determine sensitivity to ferroptosis induction.
- Inhibition of the EGFR signaling pathway using AG1498.
Main Results:
- TMZ-resistant GBM cells exhibited resistance to ferroptosis induction by RSL3, despite induced lipid peroxidation.
- ALDH1A3 expression was downregulated in TMZ-resistant cells.
- Upregulation of ALDH1A3 following TMZ withdrawal re-sensitized cells to ferroptosis.
- EGFR-dependent PI3K/Akt pathway activation correlated with ALDH1A3 recovery; EGFR inhibition reduced ALDH1A3 expression.
Conclusions:
- ALDH1A3 downregulation contributes to ferroptosis resistance in TMZ-resistant glioblastoma.
- Restoration of ALDH1A3 expression, potentially via EGFR signaling, can re-sensitize glioblastoma cells to ferroptosis.
- Targeting ALDH1A3 and ferroptosis pathways may offer new therapeutic strategies for glioblastoma relapse.
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