title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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 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.
  
  
  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.
authors.affiliation: Department of Medicine, University of Padova, Via Giustiniani 2, Padova 35128, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Manni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Brancalion
authors.forename: Laura Quotti
authors.initials: LQ
authors.lastname: Tubi
authors.forename: Anna
authors.initials: A
authors.lastname: Colpo
authors.forename: Laura
authors.initials: L
authors.lastname: Pavan
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.forename: Elisa
authors.initials: E
authors.lastname: Ave
authors.forename: Fortunato
authors.initials: F
authors.lastname: Zaffino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Maira
authors.forename: Maria
authors.initials: M
authors.lastname: Ruzzene
authors.forename: Fausto
authors.initials: F
authors.lastname: Adami
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Pitari
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Carmela
authors.initials: C
authors.lastname: Gurrieri
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D019284:Thapsigargin; D047390:Casein Kinase II