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BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Glioblastoma | Research

Proteogenomic characterization of ferroptosis regulators reveals therapeutic potential in glioblastoma

Authors: Xinzhuang Wang, Hong Zhang, Mingchu Zhang, Xuezhi Zhang, Wenbin Mao, Ming Gao

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

Ferroptosis is iron-dependent non-apoptotic cell death, that is characterized by the excessive accumulation of lipid peroxides. Ferroptosis-inducing therapy also shows promise in the treatment of cancers. However, ferroptosis-inducing therapy for glioblastoma multiforme (GBM) is still in the exploratory stage.

Methods

We identified the differentially expressed ferroptosis regulators using Mann–Whitney U test in the proteome data from Clinical Proteomic Tumor Analysis Consortium (CPTAC). We next analyzed the effect of mutation on protein abundance. A multivariate Cox model was constructed to identify the prognostic signature.

Results

In this study, we systemically portrayed the proteogenomic landscape of ferroptosis regulators in GBM. We observed that some mutation-specific ferroptosis regulators, such as down-regulated ACSL4 in EGFR-mutated patients and up-regulated FADS2 in IDH1-mutated patients, were linked to the inhibited ferroptosis activity in GBM. To interrogate the valuable treatment targets, we performed the survival analysis and identified five ferroptosis regulators (ACSL3, HSPB1, ELAVL1, IL33, and GPX4) as the prognostic biomarkers. We also validated their efficiency in external validation cohorts. Notably, we found overexpressed protein and phosphorylation abundances of HSPB1 were poor prognosis markers for overall survival of GBM to inhibit ferroptosis activity. Alternatively, HSPB1 showed a significant association with macrophage infiltration levels. Macrophage-secreted SPP1 could be a potential activator for HSPB1 in glioma cells. Finally, we recognized that ipatasertib, a novel pan-Akt inhibitor, could be a potential drug for suppressing HSPB1 phosphorylation, inducing ferroptosis of glioma cells.

Conclusion

In summary, our study characterized the proteogenomic landscape of ferroptosis regulators and identified that HSPB1 could be a candidate target for ferroptosis-inducing therapy strategy for GBM.
Appendix
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Metadata
Title
Proteogenomic characterization of ferroptosis regulators reveals therapeutic potential in glioblastoma
Authors
Xinzhuang Wang
Hong Zhang
Mingchu Zhang
Xuezhi Zhang
Wenbin Mao
Ming Gao
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-10894-3

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