Back to Search
Start Over
Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling.
- 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.
- Subjects :
- Animals
Cell Division
Endoplasmic Reticulum Chaperone BiP
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Proteins chemistry
Phenazines
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
Antineoplastic Agents therapeutic use
Casein Kinase II antagonists & inhibitors
Naphthyridines therapeutic use
Neoplasm Proteins metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Signal Transduction
Unfolded Protein Response
Subjects
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