Protein Kinase CK2 Protects Multiple Myeloma Cells from ER Stress–Induced Apoptosis and from the Cytotoxic Effect of HSP90 Inhibition through Regulation of the Unfolded Protein Response

Abstract

Purpose: 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.Experimental Design: 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.Results: CK2 partly localized to the ER and ER stress triggered its kinase activity. CK2 inhibition reduced the levels of the ER stress sensors IRE1a and BIP/GRP78, increased phosphorylation of PERK and EIF2a, and enhanced ER stress-induced apoptosis. Simultaneous inactivation of CK2 and HSP90 resulted in a synergic anti-myeloma effect (combination index ¼ 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 IRE1a/HSP90/CDC37 complexes in multiple myeloma cells.Conclusions: 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.

Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth

“…Remarkably, CX-4945 efficacy was supported by a clear down modulation of phospho Ser529 RelA and phospho Ser13 CDC37, two well-known CK2 targets. Regarding this latter molecule, since it is an essential co-chaperone of HSP90, it will be interesting to test whether double targeting of HSP90 and CK2 would be synergic in causing NHL cell death, similarly as in MM cells, like we recently demonstrated in in vivo and in vitro models [20]. …”

“…The latter encompass B-Chronic Lymphocytic Leukemia (B-CLL) [16, 17], Mantle Cell Lymphoma (MCL) [18] and Plasma Cell Myeloma (PCM) [18, 19]. As for carcinoma cell-lines, in vitro and in vivo pre-clinical studies from our and other groups have indicated that first generation CK2 inhibitors as well as the newer CX-4945 have the potential to be novel therapeutic tools for the treatment of high CK2-expressing B cell tumors [16, 17, 20]. …”

Involvement of p38 in signal switching from autophagy to apoptosis via the PERK/eIF2α/ATF4 axis in selenite-treated NB4 cells

“…33, 34 In turn, Hsp90 expression is affected by PERK activity. 34, 35 In addition, the Hsp90–Cdc37 chaperone complex was reported to suppress the autophosphorylation of p38, acting as a specific regulator of the p38 pathway. 20 In agreement with these studies, our data demonstrated that PERK activation by selenite decreased Hsp90 expression and subsequently led to p38 autophosphorylation.…”

Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and β-catenin survival signaling pathways

“…PBMC, MM and HS-5 cell lines, primary BMSCs from patients were isolated and cultured as previously described [31, 33, 43]. Malignant CD138 + PCs and healthy B cells were isolated with EasySep™ kits (STEMCELL Technologies, USA), after achieving informed consent according to the declaration of Helsinki.…”