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

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

doi:10.3390/ijms23031784

Cited by 13 publications

(11 citation statements)

References 73 publications

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“…On the other hand, the role of altered CTSZ proteolytic activity and cellular colocalization in poor prognosis in several human cancers has also been reported [68]. In gliomas, upregulation of CTSZ enzyme activity and colocalization with the total form of γ-enolase, especially in TAMs and microglia, suggest involvement in tumour progression and therapeutic targeting [69]. Altered expression and localization of CTSZ in hepatocytes are characteristic features of primary biliary cholangitis and other cholestatic liver diseases and are implicated in the progression of primary biliary cholangitis [70].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs

Chen¹,

Duan²,

Sun³

et al. 2023

Neuroendocrinology

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Introduction Somatotroph pituitary neuroendocrine tumours (PitNETs) are characterized by complex and variable biological behaviours with unpredictable patterns of growth and invasiveness. The molecular mechanisms and reliable predictors of biological markers of invasiveness remain unknown. Methods Seventy-two acromegaly patients were consecutively enrolled. Data-independent acquisition (DIA)-based proteomics and Ingenuity Pathway Analysis (IPA) were conducted between invasive and noninvasive somatotroph PitNETs. The expression of selected biomarkers was verified in PitNET tissue, and its correlation with various clinical indicators and outcomes of these tumours was assessed. The invasive phenotypes of GH3 cells were validated in vitro. Results Patients with invasive somatotroph PitNETs were significantly younger at onset and diagnosis, with significantly higher secretion and faster growth and a lower long-term biochemical response rate than patients with noninvasive somatotroph PitNETs. Proteomic data were evaluated in a consecutively collected sample of 19 (10 invasive and 9 noninvasive somatotroph PitNETs) tumours and indicated a distinct proteomic pattern. The enriched and important pathways included IL-4, PDGF, PTEN, VEGF, PI3K/AKT, FAK and other pathways that were significantly associated with tumour proliferation, migration, and invasion. High cathepsin Z (CTSZ) expression was found in invasive somatotroph PitNETs and significantly positively correlated with parameters of tumour invasion and growth. In Ctsz-overexpressing GH3 cells, cell proliferation, invasion and migration were consequently increased. Conclusion It is more difficult for patients with invasive somatotroph PitNETs to achieve remission than those with noninvasive somatotroph PitNETs, and proteomic data analysis has revealed the high expression of CTSZ as a contributing factor to invasive transformation and poor prognosis in somatotroph PitNETs for the first time.

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Section: Discussionmentioning

confidence: 99%

Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs

Chen¹,

Duan²,

Sun³

et al. 2023

Neuroendocrinology

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“…In a fresh study that listed four subtypes of GBM, DAB2 is reported as one of the fifteen selected genes that belong to the classical (CL) subtype. S100A4 was found in the CL subtype of GBM [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Screening the Significant Hub Genes by Comparing Tumor Cells, Normoxic and Hypoxic Glioblastoma Stem-like Cell Lines Using Co-Expression Analysis in Glioblastoma

Güven

Afzal

Kazmi

2022

Genes

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Glioblastoma multiforme (GBM) is categorized by rapid malignant cellular growth in the central nervous system (CNS) tumors. It is one of the most prevailing primary brain tumors, particularly in human male adults. Even though the combination therapy comprises surgery, chemotherapy, and adjuvant therapies, the survival rate is on average 14.6 months. Glioma stem cells (GSCs) have key roles in tumorigenesis, progression, and counteracting chemotherapy and radiotherapy. In our study, firstly, the gene expression dataset GSE45117 was retrieved and differentially expressed genes (DEGs) were spotted. The co-expression network analysis was employed on DEGs to find the significant modules. The most significant module resulting from co-expression analysis was the turquoise module. The turquoise module related to the tumor cells, hypoxia, normoxic treatments of glioblastoma tumor (GBT), and GSCs were screened. Sixty-one common genes in the turquoise module were selected generated through the co-expression analysis and protein–protein interaction (PPI) network. Moreover, the GO and KEGG pathway enrichment results were studied. Twenty common hub genes were screened by the NetworkAnalyst web instrument constructed on the PPI network through the STRING database. After survival analysis via the Kaplan–Meier (KM) plotter from The Cancer Genome Atlas (TCGA) database, we identified the five most significant hub genes strongly related to the progression of GBM. We further observed these five most significant hub genes also up-regulated in another GBM gene expression dataset. The protein–protein interaction (PPI) network of the turquoise module genes was constructed and a KEGG pathway enrichments study of the turquoise module genes was performed. The VEGF signaling pathway was emphasized because of the strong link with GBM. A gene–disease association network was further constructed to demonstrate the information of the progression of GBM and other related brain neoplasms. All hub genes assessed through this study would be potential markers for the prognosis and diagnosis of GBM.

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“…The proteolytic activity of cathepsin X results in C-terminal cleavage of γ-enolase, affecting its neurotrophic activity. The interplay between cathepsin X and γ-enolase was demonstrated by a correlation between the high proteolytic activity of cathepsin X and the C-terminal cleavage of γ-enolase [ 146 ].…”

Section: The Role Of γ-Enolase In Brain Cellsmentioning

confidence: 99%

“…Moreover, potent selective irreversible (AMS36) and reversible (Z7) inhibitors of cathepsin X decreased the viability of patient-derived glioblastoma multiforme cells in vitro as well as macrophages and microglia cultured in their conditioned media. Moreover, research has indicated that cathepsin X and γ-enolase are co-localized in glioblastoma multiforme tissues, especially in macrophages and microglia [ 146 ]. These findings suggest that cathepsin X plays a role in the progression of glioblastoma multiforme and is a potential target for therapeutic interventions against this aggressive brain tumor.…”

Section: The Role Of γ-Enolase In Brain Cellsmentioning

confidence: 99%

Multifunctional roles of γ-enolase in the central nervous system: more than a neuronal marker

Horvat,

Kos,

Pišlar

2024

Cell Biosci

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Enolase, a multifunctional protein with diverse isoforms, has generally been recognized for its primary roles in glycolysis and gluconeogenesis. The shift in isoform expression from α-enolase to neuron-specific γ-enolase extends beyond its enzymatic role. Enolase is essential for neuronal survival, differentiation, and the maturation of neurons and glial cells in the central nervous system. Neuron-specific γ-enolase is a critical biomarker for neurodegenerative pathologies and neurological conditions, not only indicating disease but also participating in nerve cell formation and neuroprotection and exhibiting neurotrophic-like properties. These properties are precisely regulated by cysteine peptidase cathepsin X and scaffold protein γ1-syntrophin. Our findings suggest that γ-enolase, specifically its C-terminal part, may offer neuroprotective benefits against neurotoxicity seen in Alzheimer's and Parkinson's disease. Furthermore, although the therapeutic potential of γ-enolase seems promising, the effectiveness of enolase inhibitors is under debate. This paper reviews the research on the roles of γ-enolase in the central nervous system, especially in pathophysiological events and the regulation of neurodegenerative diseases.

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

Cited by 13 publications

References 73 publications

Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs

Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs

Screening the Significant Hub Genes by Comparing Tumor Cells, Normoxic and Hypoxic Glioblastoma Stem-like Cell Lines Using Co-Expression Analysis in Glioblastoma

Multifunctional roles of γ-enolase in the central nervous system: more than a neuronal marker

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