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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.

Authors :
Buontempo F
Orsini E
Martins LR
Antunes I
Lonetti A
Chiarini F
Tabellini G
Evangelisti C
Evangelisti C
Melchionda F
Pession A
Bertaina A
Locatelli F
McCubrey JA
Cappellini A
Barata JT
Martelli AM
Source :
Leukemia [Leukemia] 2014 Mar; Vol. 28 (3), pp. 543-53. Date of Electronic Publication: 2013 Nov 20.
Publication Year :
2014

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.

Details

Language :
English
ISSN :
1476-5551
Volume :
28
Issue :
3
Database :
MEDLINE
Journal :
Leukemia
Publication Type :
Academic Journal
Accession number :
24253024
Full Text :
https://doi.org/10.1038/leu.2013.349