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

被引:66
作者
Buontempo, F. [1 ]
Orsini, E. [1 ]
Martins, L. R. [2 ]
Antunes, I. [2 ]
Lonetti, A. [1 ]
Chiarini, F. [3 ,4 ]
Tabellini, G. [5 ]
Evangelisti, C. [1 ,3 ,4 ]
Evangelisti, C. [1 ,3 ,4 ]
Melchionda, F. [6 ]
Pession, A. [6 ]
Bertaina, A. [7 ]
Locatelli, F. [7 ]
McCubrey, J. A. [8 ]
Cappellini, A. [9 ]
Barata, J. T. [2 ]
Martelli, A. M. [1 ,3 ,4 ]
机构
[1] Univ Bologna, Dept Biomed & Neuromotor Sci, I-40126 Bologna, Italy
[2] Univ Lisbon, Fac Med, Inst Mol Med, P-1699 Lisbon, Portugal
[3] CNR, Inst Mol Genet, Pavia, Italy
[4] IOR, Muscoloskeletal Cell Biol Lab, Bologna, Italy
[5] Univ Brescia, Sch Med, Dept Mol & Translat Med, Div Expt Oncol & Immunol, Brescia, Italy
[6] Univ Bologna, S Orsola M Malpighi Hosp, Pediat Oncol & Hematol Unit Lalla Seragnoli, I-40126 Bologna, Italy
[7] IRCCS Osped Pediat Bambino Gesu, Rome, Italy
[8] E Carolina Univ, Brody Sch Med, Dept Microbiol & Immunol, Greenville, NC USA
[9] Univ Cassino, Dept Human Social & Hlth Sci, I-03043 Cassino, Italy
关键词
Akt; PTEN; T-ALL; casein kinase 2; UPR; ENDOPLASMIC-RETICULUM-STRESS; CHRONIC LYMPHOCYTIC-LEUKEMIA; GLUCOCORTICOID-RECEPTOR; SELECTIVE INHIBITOR; ANTITUMOR-ACTIVITY; MYELOID-LEUKEMIA; AKT INHIBITOR; CK2; PATHWAY; SURVIVAL;
D O I
10.1038/leu.2013.349
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:543 / 553
页数:11
相关论文
共 60 条
[1]   Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling [J].
Appenzeller-Herzog, Christian ;
Hall, Michael N. .
TRENDS IN CELL BIOLOGY, 2012, 22 (05) :274-282
[2]   Contribution of bone microenvironment to leukemogenesis and leukemia progression [J].
Ayala, F. ;
Dewar, R. ;
Kieran, M. ;
Kalluri, R. .
LEUKEMIA, 2009, 23 (12) :2233-2241
[3]   The impact of PTEN regulation by CK2 on PI3K-dependent signaling and leukemia cell survival [J].
Barata, Joao T. .
ADVANCES IN ENZYME REGULATION, VOL 51, 2011, 51 :37-49
[4]   Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency [J].
Blackburn, J. S. ;
Liu, S. ;
Raiser, D. M. ;
Martinez, S. A. ;
Feng, H. ;
Meeker, N. D. ;
Gentry, J. ;
Neuberg, D. ;
Look, A. T. ;
Ramaswamy, S. ;
Bernards, A. ;
Trede, N. S. ;
Langenau, D. M. .
LEUKEMIA, 2012, 26 (09) :2069-2078
[5]   Aberrant signalling by protein kinase CK2 in imatinib-resistant chronic myeloid leukaemia cells: Biochemical evidence and therapeutic perspectives [J].
Borgo, Christian ;
Cesaro, Luca ;
Salizzato, Valentina ;
Ruzzene, Maria ;
Massimino, Maria Lina ;
Pinna, Lorenzo A. ;
Donella-Deana, Arianna .
MOLECULAR ONCOLOGY, 2013, 7 (06) :1103-1115
[6]   QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS [J].
CHOU, TC ;
TALALAY, P .
ADVANCES IN ENZYME REGULATION, 1984, 22 :27-55
[7]   Glucocorticoid sensitivity of T-cell lymphoblastic leukemia/lymphoma is associated with glucocorticoid receptor-mediated inhibition of Notch1 expression [J].
Cialfi, S. ;
Palermo, R. ;
Manca, S. ;
Checquolo, S. ;
Bellavia, D. ;
Pelullo, M. ;
Quaranta, R. ;
Donninic, C. ;
Gulino, A. ;
Screpanti, I. ;
Talora, C. .
LEUKEMIA, 2013, 27 (02) :485-488
[8]   Novel TAL1 targets beyond protein-coding genes: identification of TAL1-regulated microRNAs in T-cell acute lymphoblastic leukemia [J].
Correia, N. C. ;
Durinck, K. ;
Leite, A. P. ;
Ongenaert, M. ;
Rondou, P. ;
Speleman, F. ;
Enguita, F. J. ;
Barata, J. T. .
LEUKEMIA, 2013, 27 (07) :1603-1606
[9]   Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells [J].
Davenport, Emma L. ;
Moore, Hannah E. ;
Dunlop, Alan S. ;
Sharp, Swee Y. ;
Workman, Paul ;
Morgan, Gareth J. ;
Davies, Faith E. .
BLOOD, 2007, 110 (07) :2641-2649
[10]   Inhibition of Akt Potentiates 2-DG-Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia [J].
DeSalvo, Joanna ;
Kuznetsov, Jeffim N. ;
Du, Jianfeng ;
Leclerc, Gilles M. ;
Leclerc, Guy J. ;
Lampidis, Theodore J. ;
Barredo, Julio C. .
MOLECULAR CANCER RESEARCH, 2012, 10 (07) :969-978