Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: Turning offthe prosurvival ER chaperone BIP/Grp78 and turning on the proapoptotic NF-κB

Francesca Buontempo, Ester Orsini, Annalisa Lonetti, Alessandra Cappellini, Francesca Chiarini, Camilla Evangelisti, Cecilia Evangelisti, Fraia Melchionda, Andrea Pession, Alice Bertaina, Franco Locatelli, Jessika Bertacchini, Luca Maria Neri, James A. McCubrey, Alberto Maria Martelli

Research output: Contribution to journalArticle

Abstract

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 bortezomibmediated 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.

Original languageEnglish
Pages (from-to)1323-1340
Number of pages18
JournalOncotarget
Volume7
Issue number2
DOIs
Publication statusPublished - 2016

Keywords

  • Acute lymphoblastic leukemia
  • BIP/Grp78
  • CK2
  • NF-κB
  • Unfolded protein response

ASJC Scopus subject areas

  • Oncology

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