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

F. Buontempo, E. Orsini, L. R. Martins, I. Antunes, A. Lonetti, F. Chiarini, G. Tabellini, C. Evangelisti, C. Evangelisti, F. Melchionda, A. Pession, A. Bertaina, F. Locatelli, J. A. Mccubrey, A. Cappellini, J. T. Barata, A. M. Martelli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)543-553
Number of pages11
JournalLeukemia
Volume28
Issue number3
DOIs
Publication statusPublished - 2014

    Fingerprint

Keywords

  • Akt
  • Casein kinase 2
  • PTEN
  • T-ALL
  • UPR

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Buontempo, F., Orsini, E., Martins, L. R., Antunes, I., Lonetti, A., Chiarini, F., Tabellini, G., Evangelisti, C., Evangelisti, C., Melchionda, F., Pession, A., Bertaina, A., Locatelli, F., Mccubrey, J. A., Cappellini, A., Barata, J. T., & Martelli, A. M. (2014). Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: Targeting the unfolded protein response signaling. Leukemia, 28(3), 543-553. https://doi.org/10.1038/leu.2013.349