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Molecular Targets for Therapy

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

Leukemia volume 28, pages 543–553 (2014)Cite this article

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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.

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Acknowledgements

We thank Cylene Pharmaceuticals for generously providing CX-4945 for our in vivo studies. This work was supported by a grant from MIUR FIRB 2010 (RBAP10447J_003) to AMM and by grants PTDC/SAU-OBD/104816/2008 and PTDC/SAU-ONC/113202/2009 from Fundação para a Ciência e a Tecnologia (FCT), Portugal, to JTB. LRM and IA received FCT-SFRH PhD and Post-Doc fellowships, respectively. FL was supported by Special Project AIRC 5x1000 n. 9962 and Progetto di rilevante Interesse Nazionale, PRIN 2010.

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Authors and Affiliations

  1. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

    F Buontempo, E Orsini, A Lonetti, C Evangelisti & A M Martelli

  2. Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    L R Martins, I Antunes & J T Barata

  3. Institute of Molecular Genetics, National Research Council, Pavia, Italy

    F Chiarini, C Evangelisti & A M Martelli

  4. Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy

    F Chiarini, C Evangelisti & A M Martelli

  5. Division of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy

    G Tabellini

  6. Pediatric Oncology and Hematology Unit ‘Lalla Seràgnoli’, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

    F Melchionda & A Pession

  7. Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

    A Bertaina & F Locatelli

  8. Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    J A McCubrey

  9. Department of Human Social and Health Sciences, University of Cassino, Cassino, Italy

    A Cappellini

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  1. F Buontempo
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Buontempo, F., Orsini, E., Martins, L. et al. Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling. Leukemia 28, 543–553 (2014). https://doi.org/10.1038/leu.2013.349

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