title: Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling.
abstract: Constitutively active casein kinase 2 (CK2) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). CK2 phosphorylates PTEN (phosphatase and tensin homolog) tumor suppressor, resulting in PTEN stabilization and functional inactivation. Downregulation of PTEN activity has an impact on PI3K/Akt/mTOR signaling, which is of fundamental importance for T-ALL cell survival. These observations lend compelling weight to the application of CK2 inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of CX-4945-a novel, highly specific, orally available, ATP-competitive inhibitor of CK2α. We show that CX-4945 treatment induced apoptosis in T-ALL cell lines and patient T lymphoblasts. CX-4945 downregulated PI3K/Akt/mTOR signaling in leukemic cells. Notably, CX-4945 affected the unfolded protein response (UPR), as demonstrated by a significant decrease in the levels of the main UPR regulator GRP78/BIP, and led to apoptosis via upregulation of the ER stress/UPR cell death mediators IRE1α and CHOP. In vivo administration of CX-4945 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth. Our findings indicate that modulation of the ER stress/UPR signaling through CK2 inhibition could be exploited for inducing apoptosis in T-ALL cells and that CX-4945 may be an efficient treatment for those T-ALLs displaying upregulation of CK2α/PI3K/Akt/mTOR signaling.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Buontempo
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Orsini
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: L R
authors.initials: LR
authors.lastname: Martins
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: I
authors.initials: I
authors.lastname: Antunes
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lonetti
authors.affiliation: 1] Institute of Molecular Genetics, National Research Council, Pavia, Italy [2] Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Chiarini
authors.affiliation: Division of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tabellini
authors.affiliation: 1] Institute of Molecular Genetics, National Research Council, Pavia, Italy [2] Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Pediatric Oncology and Hematology Unit 'Lalla Seràgnoli', S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Melchionda
authors.affiliation: Pediatric Oncology and Hematology Unit 'Lalla Seràgnoli', S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pession
authors.affiliation: Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bertaina
authors.affiliation: Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Human Social and Health Sciences, University of Cassino, Cassino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cappellini
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: J T
authors.initials: JT
authors.lastname: Barata
authors.affiliation: 1] Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy [2] Institute of Molecular Genetics, National Research Council, Pavia, Italy [3] Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D002455:Cell Division; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009287:Naphthyridines / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D010619:Phenazines; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D009287:Naphthyridines; D009363:Neoplasm Proteins; D010619:Phenazines; C555142:silmitasertib; D047390:Casein Kinase II