Protein Kinase CK2 Inhibition Down Modulates the NF-κB and STAT3 Survival Pathways, Enhances the Cellular Proteotoxic Stress and Synergistically Boosts the Cytotoxic Effect of Bortezomib on Multiple Myeloma and Mantle Cell Lymphoma Cells

Abstract

CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.

Contributors

Kristy L. Richards: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 27 September 2013

Volume: 8

Issue: 9

Affiliations

[1 ]Department of Medicine, Hematology and Clinical Immunology Branch, University of Padova, Padova, Italy

[2 ]Myeloma and Lymphoma Pathobiology Laboratory, Hematologic Malignancies Unit, Venetian Institute of Molecular Medicine, Padova, Italy

[3 ]Department of Medicine, General Pathology and Cytopathology Unit, University of Padova, Padova, Italy

University of North Carolina at Chapel Hill, United States of America

Author notes

* E-mail: francesco.piazza@ 123456unipd.it (FP) ; g.semenzato@ 123456unipd.it (GS)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: SM FP. Performed the experiments: SM AB EM LQT FZ MP RC FM A. Colpo A. Cabrelle. Analyzed the data: SM FP MP SDM FM FA RZ LT CG GS. Contributed reagents/materials/analysis tools: SM MP FM GS RZ FA LT CG. Wrote the paper: SM FP.

Article

Publisher ID: PONE-D-13-16690

DOI: 10.1371/journal.pone.0075280

PMC ID: 3785505

PubMed ID: 24086494

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Page count

Pages: 16

Funding

This study was supported by a grant from the Ministero dell'Istruzione, dell' Università e della Ricerca Scientifica (MIUR; www.miur.it) n° RBFR086EW9 (FIRB "Futuro in Ricerca") and from a University of Padova ( www.unipd.it) grant n° CPDA114940/11 "Progetti di Ricerca di Ateneo" to Francesco Piazza and from the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C., Milan; www.airc.it) to Gianpietro Semenzato. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Categories

Subject: Research Article