scholarly journals Erratum: Corrigendum: The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xin Wang ◽  
Magdalena Mazurkiewicz ◽  
Ellin-Kristina Hillert ◽  
Maria Hägg Olofsson ◽  
Stefan Pierrou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myeloma Cells ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

scholarly journals The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xin Wang ◽  
Magdalena Mazurkiewicz ◽  
Ellin-Kristina Hillert ◽  
Maria Hägg Olofsson ◽  
Stefan Pierrou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Uptake ◽  
Myeloma Cells ◽  
Bcl2 Family ◽  
Promising Strategy ◽  
Specific Protease ◽  
Xenograft Models ◽  
Ubiquitin Specific Protease ◽  
Extended Survival

Abstract Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.

scholarly journals A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

Cancer Cell ◽  
2012 ◽  
Vol 22 (3) ◽  
pp. 345-358 ◽  
Author(s):  
Dharminder Chauhan ◽  
Ze Tian ◽  
Benjamin Nicholson ◽  
K.G. Suresh Kumar ◽  
Bin Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Myeloma Cells ◽  
Molecule Inhibitor ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

The ubiquitin-specific protease 8 gene is frequently mutated in adenomas causing Cushing's disease

2015 ◽  
Author(s):  
Luis Gustavo Perez Rivas ◽  
Marily Theodoropoulou ◽  
Francesco Ferrau ◽  
Clara Nusser ◽  
Kohei Kawaguchi ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Cushing's Disease ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Betulinic Acid Enhances the Sensitivity of Multiple Myeloma Cells to Bortezomib by the Inactivation of the AKT/mTOR Pathway

2020 ◽  
Vol 18 (3) ◽  
pp. 241-246
Author(s):  
Yu Dan ◽  
Wan Sheng ◽  
Hu Lili
Keyword(s):  
Multiple Myeloma ◽  
Betulinic Acid ◽  
Myeloma Cell ◽  
Mtor Pathway ◽  
Prolonged Treatment ◽  
Myeloma Cells ◽  
Multiple Myeloma Cell ◽  
Increased Sensitivity ◽  
Colony Number ◽  
Rpmi 8226

This study aimed to investigate the mechanism of betulinic acid on multiple myeloma cell resistance to bortezomib. To this end, the bortezomib-resistant RPMI-8226-R cells were generated by prolonged treatment of RPMI-8226 cells with increasing concentrations of bortezomib. Based on the measurements of cell viability and colony number, RPMI-8226-R cells exhibited enhanced resistance to bortezomib than RPMI-8226 cells. Treatment with betulinic acid resulted in increased sensitivity of RPMI-8226-R to bortezomib. When RPMI-8226-R cells were co-treated with bortezomib and betulinic acid, there was an increase in apoptosis rate, cleaved caspase-3, cleaved caspase-9 expression and the decrease in p-AKT/AKT and p-mTOR/mTOR levels. These results suggest that betulinic acid enhances the sensitivity of RPMI-8226-R cells to bortezomib by inhibiting the activation of the AKT/mTOR pathway in bortezomib-resistant multiple myeloma cells.

USP48 Sustains Chemoresistance and Metastasis in Ovarian Cancer

2020 ◽  
Vol 20 (9) ◽  
pp. 689-699
Author(s):  
Xuemeng Lei ◽  
Xukun Li ◽  
Hongyan Chen ◽  
Zhihua Liu
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Deubiquitinating Enzymes ◽  
Potential Therapeutic Target ◽  
Kaplan Meier ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Background: Ubiquitin specific protease 48 (USP48) is a member of the deubiquitinating enzymes (DUBs) family. However, the function of USP48 in ovarian cancer remains unclear. Objective: The present study reveals that USP48 knockdown could significantly inhibit cell migration and invasion in ES2, 3AO and A2780 cells, without affecting cell proliferation. Methods: After carboplatin (CBP) treatment, the USP48 ablation increases the apoptosis rate, and the cleaved PARP and cleaved caspase 3 expression levels in ES2, 3AO and A2780 cells. The subcutaneous tumor and intraperitoneally injected experiments demonstrated that the USP48 knockdown significantly increases responsiveness to CBP, and alleviates the metastasis in vivo. Meanwhile, USP48 deficiency results in the improved survival of mice. Results: Finally, the analysis of clinical samples and the TCGA and Kaplan-Meier Plot database revealed that the high expression of USP48 in ovarian cancer patients is associated with poor survival and resistance to CBP therapy. Conclusion: In summary, USP48 may be a potential therapeutic target for ovarian cancer patients.

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