Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling

• Published in: Leukemia Vol. 28; no. 3; pp. 543 - 553
• Main Authors: Buontempo, F, Orsini, E, Martins, L R, Antunes, I, Lonetti, A, Chiarini, F, Tabellini, G, Evangelisti, C, Melchionda, F, Pession, A, Bertaina, A, Locatelli, F, McCubrey, J A, Cappellini, A, Barata, J T, Martelli, A M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2014
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; AKT protein; Animals; Antineoplastic Agents - therapeutic use; Apoptosis; Cancer therapies; Casein; Casein kinase II; Casein Kinase II - antagonists & inhibitors; Cell death; Cell Division; Cell survival; Cytotoxicity; Development and progression; Drug therapy; Enzyme inhibitors; Homology; Humans; Immunology; Inactivation; Kinases; Leukemia; Leukemia research; Lymphatic leukemia; Lymphoblasts; Lymphocytes T; Medical prognosis; Mice; Mice, Inbred NOD; Mice, SCID; Naphthyridines - therapeutic use; Neoplasm Proteins - chemistry; Neoplasm Proteins - metabolism; Oncology; Patients; Phosphatase; Physiological aspects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein folding; Protein kinases; Proteins; PTEN protein; Signal Transduction; Signaling; T cells; Tensin; TOR protein; Tumor suppressor genes; Tumors; Unfolded Protein Response; Xenografts; Xenotransplantation; United States > US; Italy
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.349

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.