title: Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity.
abstract: BACKGROUND
  The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications also in the resistance to conventional and unconventional therapies. Moreover, CK2 role in blood tumors is rapidly emerging and this kinase has been recognized as a potential therapeutic target. Phase I clinical trials with the oral small ATP-competitive CK2 inhibitor CX-4945 are currently ongoing in solid tumors and multiple myeloma.
  
  
  METHODS
  We have analyzed the expression of CK2 in acute myeloid leukemia and its function in cell growth and in the response to the chemotherapeutic agent daunorubicin We employed acute myeloid leukemia cell lines and primary blasts from patients grouped according to the European LeukemiaNet risk classification. Cell survival, apoptosis and sensitivity to daunorubicin were assessed by different means. p53-dependent CK2-inhibition-induced apoptosis was investigated in p53 wild-type and mutant cells.
  
  
  RESULTS
  CK2a was found highly expressed in the majority of samples across the different acute myeloid leukemia prognostic subgroups as compared to normal CD34+ hematopoietic and bone marrow cells. Inhibition of CK2 with CX-4945, K27 or siRNAs caused a p53-dependent acute myeloid leukemia cell apoptosis. CK2 inhibition was associated with a synergistic increase of the cytotoxic effects of daunorubicin. Baseline and daunorubicin-induced STAT3 activation was hampered upon CK2 blockade.
  
  
  CONCLUSIONS
  These results suggest that CK2 is over expressed across the different acute myeloid leukemia subsets and acts as an important regulator of acute myeloid leukemia cell survival. CK2 negative regulation of the protein levels of tumor suppressor p53 and activation of the STAT3 anti-apoptotic pathway might antagonize apoptosis and could be involved in acute myeloid leukemia cell resistance to daunorubicin.
authors.forename: Laura
authors.initials: L
authors.lastname: Quotti Tubi
authors.forename: Carmela
authors.initials: C
authors.lastname: Gurrieri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Brancalion
authors.forename: Laura
authors.initials: L
authors.lastname: Bonaldi
authors.forename: Roberta
authors.initials: R
authors.lastname: Bertorelle
authors.forename: Sabrina
authors.initials: S
authors.lastname: Manni
authors.forename: Laura
authors.initials: L
authors.lastname: Pavan
authors.forename: Federica
authors.initials: F
authors.lastname: Lessi
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
authors.forename: Fausto
authors.initials: F
authors.lastname: Adami
authors.forename: Maria
authors.initials: M
authors.lastname: Ruzzene
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009287:Naphthyridines / Q000494:pharmacology*; D010619:Phenazines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D009287:Naphthyridines; D010619:Phenazines; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C555142:silmitasertib; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; D003630:Daunorubicin