Oncotarget

Research Papers:

Acute lymphoblastic leukemia cells are sensitive to disturbances in protein homeostasis induced by proteasome deubiquitinase inhibition

Magdalena Mazurkiewicz, Ellin-Kristina Hillert, Xin Wang, Paola Pellegrini, Maria Hägg Olofsson, Karthik Selvaraju, Padraig D’Arcy and Stig Linder _

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Oncotarget. 2017; 8:21115-21127. https://doi.org/10.18632/oncotarget.15501

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Abstract

Magdalena Mazurkiewicz1, Ellin-Kristina Hillert1, Xin Wang2, Paola Pellegrini2, Maria Hägg Olofsson1, Karthik Selvaraju2, Padraig D’Arcy2, Stig Linder1,2

1Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden

2Department of Medical Health Sciences (IMH), Linköping University, S-751 85 Linköping, Sweden

Correspondence to:

Stig Linder, email: [email protected]

Keywords: acute lymphoblastic leukemia, proteasome, deubiquitinase, ER stress, VLX1570

Received: December 02, 2016     Accepted: February 07, 2017     Published: February 18, 2017

ABSTRACT

The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability. VLX1570 treatment increased the levels of a number of proteins, including the chaperone HSP70B’, the oxidative stress marker heme oxygenase-1 (HO-1) and the cell cycle regulator p21Cip1. Unexpectedly, polyubiquitin accumulation was found to be uncoupled from ER stress in ALL cells. Thus, increased phosphorylation of eIF2α occurred only at supra-pharmacological VLX1570 concentrations and did not correlate with polyubiquitin accumulation. Total cellular protein synthesis was found to decrease in the absence of eIF2α phosphorylation. Furthermore, ISRIB (Integrated Stress Response inhibitor) did not overcome the inhibition of protein synthesis. We finally show that VLX1570 can be combined with L-asparaginase for additive or synergistic antiproliferative effects on ALL cells. We conclude that ALL cells are highly sensitive to the proteasome DUB inhibitor VLX1570 suggesting a novel therapeutic option for this disease.


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