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Upregulation of Cathepsin X in Glioblastoma: Interplay with γ-Enolase and the Effects of Selective Cathepsin X Inhibitors

Authors :
Bernarda Majc
Anamarija Habič
Metka Novak
Ana Rotter
Andrej Porčnik
Jernej Mlakar
Vera Župunski
Urša Pečar Fonović
Damijan Knez
Nace Zidar
Stanislav Gobec
Janko Kos
Tamara Lah Turnšek
Anja Pišlar
Barbara Breznik
Source :
International Journal of Molecular Sciences, Vol 23, Iss 3, p 1784 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Understanding GBM pathobiology and discovering novel therapeutic targets are critical to finding efficient treatments. Upregulation of the lysosomal cysteine carboxypeptidase cathepsin X has been linked to immune dysfunction and neurodegenerative diseases, but its role in cancer and particularly in GBM progression in patients is unknown. In this study, cathepsin X expression and activity were found to be upregulated in human GBM tissues compared to low-grade gliomas and nontumor brain tissues. Cathepsin X was localized in GBM cells as well as in tumor-associated macrophages and microglia. Subsequently, potent irreversible (AMS36) and reversible (Z7) selective cathepsin X inhibitors were tested in vitro. Selective cathepsin X inhibitors decreased the viability of patient-derived GBM cells as well as macrophages and microglia that were cultured in conditioned media of GBM cells. We next examined the expression pattern of neuron-specific enzyme γ-enolase, which is the target of cathepsin X. We found that there was a correlation between high proteolytic activity of cathepsin X and C-terminal cleavage of γ-enolase and that cathepsin X and γ-enolase were colocalized in GBM tissues, preferentially in GBM-associated macrophages and microglia. Taken together, our results on patient-derived material suggest that cathepsin X is involved in GBM progression and is a potential target for therapeutic approaches against GBM.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
23
Issue :
3
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.bb38ce05823b4a539b90db8efbba8a54
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms23031784