Abstract
Protein kinase CK2 promotes multiple myeloma cell growth by regulating critical signaling pathways. CK2 also modulates proper HSP90-dependent client protein folding and maturation by phosphorylating its co-chaperone CDC37. Because the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is central in myeloma pathogenesis, we tested the hypothesis that the CK2/CDC37/HSP90 axis could be involved in UPR in myeloma cells. We analyzed CK2 activity upon ER stress, the effects of its inactivation on the UPR pathways and on ER stress-induced apoptosis. The consequences of CK2 plus HSP90 inhibition on myeloma cell growth in vitro and in vivo and CK2 regulation of HSP90-triggered UPR were determined. CK2 partly localized to the ER and ER stress triggered its kinase activity. CK2 inhibition reduced the levels of the ER stress sensors IRE1α and BIP/GRP78, increased phosphorylation of PERK and EIF2α, and enhanced ER stress-induced apoptosis. Simultaneous inactivation of CK2 and HSP90 resulted in a synergic anti-myeloma effect (combination index = 0.291) and in much stronger alterations of the UPR pathways as compared with the single inhibition of the two molecules. Cytotoxicity from HSP90 and CK2 targeting was present in a myeloma microenvironment model, on plasma cells from patients with myeloma and in an in vivo mouse xenograft model. Mechanistically, CK2 inhibition led to a reduction of IRE1α/HSP90/CDC37 complexes in multiple myeloma cells. Our results place CK2 as a novel regulator of the ER stress/UPR cascades and HSP90 function in myeloma cells and offer the groundwork to design novel combination treatments for this disease.
Highlights
Significant progresses in understanding the pathogenesis of multiple myeloma—an incurable B-cell malignancy that originates from plasma cells [1]—prompted to test different molecules as therapeutic targets [2].Authors' Affiliations: 1Department of Medicine, Clinical Immunology and Hematology Branches; 2Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica; 3Department of Biological Chemistry, University of Padova, Padova; and 4Medical Oncology Unit, Magna Graecia University, Catanzaro, ItalyNote: Supplementary data for this article are available at Clinical Cancer Research Online.We described that protein kinase CK2 is crucial for multiple myeloma cell survival, positively regulates STAT3 and NF-kB signaling, and controls multiple myeloma cell sensitivity to melphalan [3]
CK2 inhibition reduced the levels of the endoplasmic reticulum (ER) stress sensors IRE1a and BIP/GRP78, increased phosphorylation of PERK and EIF2a, and enhanced ER stress–induced apoptosis
CK2 inhibition led to a reduction of IRE1a/HSP90/CDC37 complexes in multiple myeloma cells
Summary
The molecular chaperone HSP90 plays a pivotal role in protein folding, maturation, and cell survival [6]. Multiple myeloma plasma cells are exquisitely sensitive to cytotoxicity of HSP90 inhibitors such as geldanamycin and its derivatives [7,8,9,10,11]. CK2 regulates the activity of the chaperone complex formed by CDC37 and HSP90 by phosphorylating Ser on CDC37 [12]. This phosphorylation promotes the association of HSP90 with client proteins, in particular protein kinases [13]. HSP90 takes part in the endoplasmic reticulum (ER) stress–induced unfolded
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