New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Mitrović, Ana; Senjor, Emanuela; Jukič, Marko; Bolčina, Lara; Prunk, Mateja; Proj, Matic; Nanut, Milica Perišić; Gobec, Stanislav; Kos, Janko

doi:10.1016/j.csbj.2022.08.046

Cited by 6 publications

(4 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recently, a virtual high-throughput strategy was used to screen commercial compound libraries to identify new inhibitors targeting CTSV. While some of the most potent CTSV inhibitors identified could also target CTSL, compound 7 from the study did show selectivity towards CTSV and examination in cell-based assays illustrated its ability to attenuate MCF-7 tumour cell proliferation, in line with our observations herein using shRNAs (Mitrović et al, 2022).…”

Section: Discussionsupporting

confidence: 77%

Cathepsin V regulates cell cycle progression and histone stability in the nucleus of breast cancer cells

Sereesongsaeng,

Burrows,

Scott

et al. 2023

Front. Pharmacol.

View full text Add to dashboard Cite

Introduction: We previously identified that Cathepsin V (CTSV) expression is associated with poor prognosis in ER+ breast cancer, particularly within the Luminal A subtype. Examination of the molecular role of the protease within Luminal A tumours, revealed that CTSV promotes tumour cell invasion and proliferation, in addition to degradation of the luminal transcription factor, GATA3, via the proteasome.Methods: Cell line models expressing CTSV shRNA or transfected to overexpress CTSV were used to examine the impact of CTSV on cell proliferation by MTT assay and flow cytometry. Western blotting analysis was used to identify the impact of CTSV on histone and chaperone protein expression. Cell fractionation and confocal microscopy was used to illustrate the presence of CTSV in the nuclear compartment.Results: In this work we have identified that CTSV has an impact on breast cancer cell proliferation, with CTSV depleted cells exhibiting delayed progression through the G2/M phase of the cell cycle. Further investigation has revealed that CTSV can control nuclear expression levels of histones H3 and H4 via regulating protein expression of their chaperone sNASP. We have discovered that CTSV is localised to the nuclear compartment in breast tumour cells, mediated by a bipartite nuclear localisation signal (NLS) within the CTSV sequence and that nuclear CTSV is required for cell cycle progression and histone stability in breast tumour cells.Discussion: Collectively these findings support the hypothesis that targeting CTSV may have utility as a novel therapeutic target in ER+ breast cancer by impairing cell cycle progression via manipulating histone stabilisation.

show abstract

Section: Discussionsupporting

confidence: 77%

Cathepsin V regulates cell cycle progression and histone stability in the nucleus of breast cancer cells

Sereesongsaeng,

Burrows,

Scott

et al. 2023

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Inhibitors of CTSV have recently been developed and found to be effective in boosting the immunological response to tumors that reduced tumor-cell proliferation and elastin breakdown and blocking cystatin F (CysF) activation (Senjor, Kos, and Nanut 2023). While cathepsins V and L share a genetic locus on the human chromosome, 9q22.2, their tissue distribution, binding site architecture, substrate selectivity, and functions are distinct (Mitrović et al, 2022). Due to its ability to facilitate GATA3's turnover via the proteasome, cathepsin V can reduce GATA3 expression in ER-positive breast cancers, restoring GATA3 protein expression, which is associated with a better prognosis, and making cathepsin V targeting a practical treatment option in ER-positive breast tumors (Sereesongsaeng et al, 2020).…”

Section: Cathepsin V (Ctsv)mentioning

confidence: 99%

Cysteine Cathepsins and Their Diagnostic Role in Breast Cancer

Hosney,

Sarhan

2024

Egyptian Academic Journal of Biological Sciences. C, Physiology

View full text Add to dashboard Cite

Background: A large class of proteolytic enzymes known as cysteine cathepsins are created as pro-enzymes and are activated in slightly acidic conditions. They are crucial for both healthy cellular function and illness. Cysteine cathepsins are a family of proteases that play important roles in a variety of cellular processes, including protein turnover, cell adhesion, and migration. Main body: In breast cancer, cysteine cathepsins have been shown to be overexpressed in tumor cells and to be associated with poor prognosis. This review article discusses the role of cysteine cathepsins in breast cancer, focusing on their diagnostic potential. The article provides an overview of cysteine cathepsins, including their structure, function, and regulation in addition to the evidence for the overexpression of cysteine cathepsins in breast cancer and their association with a poor prognosis. Conclusions: The current review demonstrates the potential use of cysteine cathepsins as biomarkers for early detection and diagnosis of breast cancer.

show abstract

“…; Table S3: Cancer Hallmark GeneSets associated with Valproic acid (VPA) administration; Table S4: Results of online sample size calculation tool to calculate the minimum sample size for PFS and OS. References [73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92] were cited in Supplementary Materials.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Revisiting Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients with Glioblastoma—Proteomic Alteration and Comparison Analysis with the Standard-of-Care Chemoirradiation

Krauze,

Zhao,

et al. 2023

Biomolecules

View full text Add to dashboard Cite

Background: Glioblastoma (GBM) is the most common brain tumor with an overall survival (OS) of less than 30% at two years. Valproic acid (VPA) demonstrated survival benefits documented in retrospective and prospective trials, when used in combination with chemo-radiotherapy (CRT). Purpose: The primary goal of this study was to examine if the differential alteration in proteomic expression pre vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA as compared to standard-of-care CRT. The second goal was to explore the associations between the proteomic alterations in response to VPA/RT/TMZ correlated to patient outcomes. The third goal was to use the proteomic profile to determine the mechanism of action of VPA in this setting. Materials and Methods: Serum obtained pre- and post-CRT was analyzed using an aptamer-based SOMAScan® proteomic assay. Twenty-nine patients received CRT plus VPA, and 53 patients received CRT alone. Clinical data were obtained via a database and chart review. Tests for differences in protein expression changes between radiation therapy (RT) with or without VPA were conducted for individual proteins using two-sided t-tests, considering p-values of <0.05 as significant. Adjustment for age, sex, and other clinical covariates and hierarchical clustering of significant differentially expressed proteins was carried out, and Gene Set Enrichment analyses were performed using the Hallmark gene sets. Univariate Cox proportional hazards models were used to test the individual protein expression changes for an association with survival. The lasso Cox regression method and 10-fold cross-validation were employed to test the combinations of expression changes of proteins that could predict survival. Predictiveness curves were plotted for significant proteins for VPA response (p-value < 0.005) to show the survival probability vs. the protein expression percentiles. Results: A total of 124 proteins were identified pre- vs. post-CRT that were differentially expressed between the cohorts who received CRT plus VPA and those who received CRT alone. Clinical factors did not confound the results, and distinct proteomic clustering in the VPA-treated population was identified. Time-dependent ROC curves for OS and PFS for landmark times of 20 months and 6 months, respectively, revealed AUC of 0.531, 0.756, 0.774 for OS and 0.535, 0.723, 0.806 for PFS for protein expression, clinical factors, and the combination of protein expression and clinical factors, respectively, indicating that the proteome can provide additional survival risk discrimination to that already provided by the standard clinical factors with a greater impact on PFS. Several proteins of interest were identified. Alterations in GALNT14 (increased) and CCL17 (decreased) (p = 0.003 and 0.003, respectively, FDR 0.198 for both) were associated with an improvement in both OS and PFS. The pre-CRT protein expression revealed 480 proteins predictive for OS and 212 for PFS (p < 0.05), of which 112 overlapped between OS and PFS. However, FDR-adjusted p values were high, with OS (the smallest p value of 0.586) and PFS (the smallest p value of 0.998). The protein PLCD3 had the lowest p-value (p = 0.002 and 0.0004 for OS and PFS, respectively), and its elevation prior to CRT predicted superior OS and PFS with VPA administration. Cancer hallmark genesets associated with proteomic alteration observed with the administration of VPA aligned with known signal transduction pathways of this agent in malignancy and non-malignancy settings, and GBM signaling, and included epithelial–mesenchymal transition, hedgehog signaling, Il6/JAK/STAT3, coagulation, NOTCH, apical junction, xenobiotic metabolism, and complement signaling. Conclusions: Differential alteration in proteomic expression pre- vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA. Using pre- vs. post-data, prognostic proteins emerged in the analysis. Using pre-CRT data, potentially predictive proteins were identified. The protein signals and hallmark gene sets associated with the alteration in the proteome identified between patients who received VPA and those who did not, align with known biological mechanisms of action of VPA and may allow for the identification of novel biomarkers associated with outcomes that can help advance the study of VPA in future prospective trials.

show abstract

New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Cited by 6 publications

References 63 publications

Cathepsin V regulates cell cycle progression and histone stability in the nucleus of breast cancer cells

Cathepsin V regulates cell cycle progression and histone stability in the nucleus of breast cancer cells

Cysteine Cathepsins and Their Diagnostic Role in Breast Cancer

Revisiting Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients with Glioblastoma—Proteomic Alteration and Comparison Analysis with the Standard-of-Care Chemoirradiation

Contact Info

Product

Resources

About