Sabrina Manni 1 , 2 , Alessandra Brancalion 1 , 2 , Elisa Mandato 1 , 2 , Laura Quotti Tubi 1 , 2 , Anna Colpo 1 , 2 , Marco Pizzi 3 , Rocco Cappellesso 3 , Fortunato Zaffino 1 , 2 , Speranza Antonia Di Maggio 1 , Anna Cabrelle 2 , Filippo Marino 3 , Renato Zambello 1 , 2 , Livio Trentin 1 , 2 , Fausto Adami 1 , Carmela Gurrieri 1 , 2 , Gianpietro Semenzato 1 , 2 , * , Francesco Piazza 1 , 2 , *
27 September 2013
CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.