Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.11340
Title: Exocytosis of polyubiquitinated proteins in bortezomib-resistant leukemia cells: A role for MARCKS in acquired resistance to proteasome inhibitors
Authors: Franke, N.E
Kaspers, G.L
Assaraf, Y.G
Meerloo, J
Niewerth, D
Kessler, F.L
Poddighe, P.J
Kole, J
Smeets, S.J
Ylstra, B
Bi, C
Chng, W.J 
Horton, T.M
Menezes, R.X
Musters, R.J.P
Zweegman, S
Jansen, G
Cloos, J
Keywords: asparaginase macrogol
bortezomib
cyclophosphamide
DNA
doxorubicin
etoposide
MARCKS protein
messenger RNA
methotrexate
microRNA
prednisone
ubiquitin
vincristine
antineoplastic agent
bortezomib
MARCKS protein
microRNA
proteasome inhibitor
ubiquitin
acute lymphoblastic leukemia
Article
cancer prognosis
CCRF CEM cell line
controlled study
down regulation
exocytosis
gene expression profiling
gene expression regulation
human
human cell
in vitro study
leukemia cell
MARCKS gene
microarray analysis
oncogene
protein degradation
protein expression
upregulation
comparative genomic hybridization
drug resistance
gene regulatory network
genetics
leukemia
metabolism
mortality
prognosis
tumor cell line
ubiquitination
Antineoplastic Agents
Bortezomib
Cell Line, Tumor
Comparative Genomic Hybridization
Drug Resistance, Neoplasm
Exocytosis
Gene Expression Profiling
Gene Expression Regulation, Leukemic
Gene Regulatory Networks
Humans
Leukemia
MicroRNAs
Myristoylated Alanine-Rich C Kinase Substrate
Prognosis
Proteasome Inhibitors
Ubiquitin
Ubiquitination
Up-Regulation
Issue Date: 2016
Citation: Franke, N.E, Kaspers, G.L, Assaraf, Y.G, Meerloo, J, Niewerth, D, Kessler, F.L, Poddighe, P.J, Kole, J, Smeets, S.J, Ylstra, B, Bi, C, Chng, W.J, Horton, T.M, Menezes, R.X, Musters, R.J.P, Zweegman, S, Jansen, G, Cloos, J (2016). Exocytosis of polyubiquitinated proteins in bortezomib-resistant leukemia cells: A role for MARCKS in acquired resistance to proteasome inhibitors. Oncotarget 7 (46) : 74779-74796. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.11340
Abstract: PSMB5 mutations and upregulation of the ?5 subunit of the proteasome represent key determinants of acquired resistance to the proteasome inhibitor bortezomib (BTZ) in leukemic cells in vitro. We here undertook a multi-modality (DNA, mRNA, miRNA) array-based analysis of human CCRF-CEM leukemia cells and BTZ-resistant subclones to determine whether or not complementary mechanisms contribute to BTZ resistance. These studies revealed signatures of markedly reduced expression of proteolytic stress related genes in drug resistant cells over a broad range of BTZ concentrations along with a high upregulation of myristoylated alanine-rich C-kinase substrate (MARCKS) gene expression. MARCKS upregulation was confirmed on protein level and also observed in other BTZ-resistant tumor cell lines as well as in leukemia cells with acquired resistance to other proteasome inhibitors. Moreover, when MARCKS protein expression was demonstrated in specimens derived from therapyrefractory pediatric leukemia patients (n = 44), higher MARCKS protein expression trended (p = 0.073) towards a dismal response to BTZ-containing chemotherapy. Mechanistically, we show a BTZ concentration-dependent association of MARCKS protein levels with the emergence of ubiquitin-containing vesicles in BTZ-resistant CEM cells. These vesicles were found to be extruded and taken up in co-cultures with proteasome-proficient acceptor cells. Consistent with these observations, MARCKS protein associated with ubiquitin-containing vesicles was also more prominent in clinical leukemic specimen with ex vivo BTZ resistance compared to BTZ-sensitive leukemia cells. Collectively, we propose a role for MARCKS in a novel mechanism of BTZ resistance via exocytosis of ubiquitinated proteins in BTZ-resistant cells leading to quenching of proteolytic stress.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174104
ISSN: 19492553
DOI: 10.18632/oncotarget.11340
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