20.500.12556/RUL-137355 Upregulation of cathepsin X in glioblastoma interplay with γ-enolase and the effects of selective cathepsin X inhibitors 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. glioblastoma cathepsin X γ-enolase tumor microenvironment glioblastoma stem cells cathepsin X inhibitors true false true Angleški jezik Ni določen Članek v reviji 2022-06-14 08:18:39 2022-06-14 08:18:40 2022-09-15 04:14:58 0000-00-00 00:00:00 2022 0 0 20 str. iss. 3, art. 1784 Vol. 23 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577 1422-0067 10.3390/ijms23031784 96442883 ijms-23-01784-v2.pdf ijms-23-01784-v2.pdf 1 0F98353B3F64E63E4D616812B74D0D94 b1fabd375942e9f0d2c7a7f35668df4889a12aa7601bce97b425e22d9c05cf23 ec1dc39a-eba9-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=157288 https://www.mdpi.com/1422-0067/23/3/1784 1 aa53d791-eba9-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=157287 Medicinska fakulteta Fakulteta za kemijo in kemijsko tehnologijo Fakulteta za farmacijo 0 0 0