Upregulation of cathepsin X in glioblastoma : interplay with γ-enolase and the effects of selective cathepsin X inhibitors

Majc, Bernarda (author), Habič, Anamarija (author), Novak, Metka (author), Rotter, Ana (author), Porčnik, Andrej (author), Mlakar, Jernej (author), Župunski, Vera (author), Pečar Fonović, Urša (author), Knez, Damijan (author), Zidar, Nace (author), Gobec, Stanislav (author), Kos, Janko (author), Lah Turnšek, Tamara (author), Pišlar, Anja (author), Breznik, Barbara (author)

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 patientderived 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.

• Language: English
• Keywords: glioblastoma, cathepsin X, γ-enolase, tumor microenvironment, glioblastoma stem cells, cathepsin X inhibitors
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine; FKKT - Faculty of Chemistry and Chemical Technology; FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 20 str.
• Numbering: Vol. 23, iss. 3, art. 1784
• PID: 20.500.12556/RUL-137355
• UDC: 577
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms23031784
• COBISS.SI-ID: 96442883
• Publication date in RUL: 14.06.2022

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

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• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 04.02.2022