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

Xin Wang, Magdalena Mazurkiewicz, Ellin Kristina Hillert, Maria Hägg Olofsson, Stefan Pierrou, Per Hillertz, Joachim Gullbo, Karthik Selvaraju, Aneel Paulus, Sharoon Akhtar, Felicitas Bossler, Asher A Chanan Khan, Stig Linder, Padraig D'Arcy

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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.

Original languageEnglish (US)
Article number26979
JournalScientific Reports
Volume6
DOIs
StatePublished - Jun 6 2016

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Ubiquitin-Specific Proteases
Proteasome Inhibitors
Multiple Myeloma
Apoptosis
Ubiquitin Thiolesterase
Proto-Oncogene Proteins c-bcl-2
Polyubiquitin
Caspase Inhibitors
Electroporation
Proteasome Endopeptidase Complex
Heterografts
Small Interfering RNA
Deubiquitinating Enzymes
Molecular Weight
Clinical Trials
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

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The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. / Wang, Xin; Mazurkiewicz, Magdalena; Hillert, Ellin Kristina; Olofsson, Maria Hägg; Pierrou, Stefan; Hillertz, Per; Gullbo, Joachim; Selvaraju, Karthik; Paulus, Aneel; Akhtar, Sharoon; Bossler, Felicitas; Chanan Khan, Asher A; Linder, Stig; D'Arcy, Padraig.

In: Scientific Reports, Vol. 6, 26979, 06.06.2016.

Research output: Contribution to journalArticle

Wang, X, Mazurkiewicz, M, Hillert, EK, Olofsson, MH, Pierrou, S, Hillertz, P, Gullbo, J, Selvaraju, K, Paulus, A, Akhtar, S, Bossler, F, Chanan Khan, AA, Linder, S & D'Arcy, P 2016, 'The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells', Scientific Reports, vol. 6, 26979. https://doi.org/10.1038/srep26979
Wang, Xin ; Mazurkiewicz, Magdalena ; Hillert, Ellin Kristina ; Olofsson, Maria Hägg ; Pierrou, Stefan ; Hillertz, Per ; Gullbo, Joachim ; Selvaraju, Karthik ; Paulus, Aneel ; Akhtar, Sharoon ; Bossler, Felicitas ; Chanan Khan, Asher A ; Linder, Stig ; D'Arcy, Padraig. / The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. In: Scientific Reports. 2016 ; Vol. 6.
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