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

International Journal of Molecular Sciences

Vera Župunski¹  Metka Novak²  Bernarda Majc²  Anamarija Habič²  Ana Rotter²  Barbara Breznik²  Tamara Lah Turnšek²  Andrej Porčnik³  Janko Kos⁴  Nace Zidar⁴  Anja Pišlar⁴  Urša Pečar Fonović⁴  Stanislav Gobec⁴  Damijan Knez⁴  Jernej Mlakar⁵ 

[1] Chair of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, 113 Večna pot, 1000 Ljubljana, Slovenia;Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 111 Večna pot, 1000 Ljubljana, Slovenia;Department of Neurosurgery, University Medical Centre Ljubljana, 7 Zaloška cesta, 1000 Ljubljana, Slovenia;Faculty of Pharmacy, University of Ljubljana, 7 Aškerčeva cesta, 1000 Ljubljana, Slovenia;Institute of Pathology, Faculty of Medicine, University of Ljubljana, 2 Korytkova ulica, 1000 Ljubljana Slovenia;

关键词: glioblastoma;    cathepsin X;    γ-enolase;    tumor microenvironment;    glioblastoma stem cells;    cathepsin X inhibitors;   

DOI  :  10.3390/ijms23031784

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown