Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB
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Francesca Buontempo1, Ester Orsini1, Annalisa Lonetti2, Alessandra Cappellini3, Francesca Chiarini4,5, Camilla Evangelisti4,5, Cecilia Evangelisti1, Fraia Melchionda2, Andrea Pession2, Alice Bertaina6, Franco Locatelli6, Jessika Bertacchini7, Luca Maria Neri8, James A. McCubrey9 and Alberto Maria Martelli1
1 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
2 Pediatric Oncology and Hematology Unit “Lalla Seràgnoli”, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
3 Department of Human Social and Health Sciences, Campus Folcara, University of Cassino, Cassino, Italy
4 Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy
5 Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy
6 Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
7 Department of Surgery, Medicine, Odontostomatology and Morphological Sciences, University of Modena, Modena, Italy
8 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
9 Department of Microbiology and Immunology, School of Medicine, East Carolina University, Greenville, NC, USA
Alberto Maria Martelli, email:
Keywords: acute lymphoblastic leukemia, CK2, unfolded protein response, BIP/Grp78, NF-κB
Received: June 19, 2015 Accepted: November 15, 2015 Published: November 22, 2015
The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX-4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomib-mediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL.
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