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 CK2 alpha. 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 IRE1 alpha 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 CK2 alpha/PI3K/Akt/mTOR signaling.

Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling / 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. - In: LEUKEMIA. - ISSN 0887-6924. - 28:3(2014), pp. 543-553. [10.1038/leu.2013.349]

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

Chiarini, F;Melchionda, F;Cappellini, A;
2014-01-01

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 CK2 alpha. 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 IRE1 alpha 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 CK2 alpha/PI3K/Akt/mTOR signaling.
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Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling / 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. - In: LEUKEMIA. - ISSN 0887-6924. - 28:3(2014), pp. 543-553. [10.1038/leu.2013.349]
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1291849
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