Abstract
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.
Highlights
Bortezomib, a boronic acid compound targeting the chymotrypsin-like activity of the 26S subunit of the proteasome, is a firstin class proteasome inhibitor (PI) [1], which has demonstrated remarkable activity against multiple myeloma (MM) and mantle cell lymphoma (MCL), two yet incurable hematologic malignancies [2,3,4]
To investigate the expression of CK2 in bortezomib-sensitive B cell tumors, the expression of CK2a and CK2b proteins were examined by immunohistochemistry in lymph node biopsies from MCL patients (n = 21), in normal lymphoid tissues(n = 3), in bone marrow biopsies obtained from monoclonal gammopathy of undetermined significance (MGUS) (n = 5) and MM patients (n = 17)
We showed here that protein kinase CK2 is highly expressed in MM and MCL and its inhibition enhances MM and MCL cells sensitivity to the proteasome inhibitor bortezomib
Summary
Bortezomib, a boronic acid compound targeting the chymotrypsin-like activity of the 26S subunit of the proteasome, is a firstin class proteasome inhibitor (PI) [1], which has demonstrated remarkable activity against multiple myeloma (MM) and mantle cell lymphoma (MCL), two yet incurable hematologic malignancies [2,3,4]. It stabilizes the tumor suppressor p53 and the pro-apoptotic protein Bax and up regulates the proteins Noxa and Puma [11], while it induces cleavage and inactivation of the anti-apoptotic molecule Mcl1 [12,13], thereby causing the activation of the mitochondriadependent apoptosis. A number of studies have shown that CK2 over-expression may force the cell to acquire a pro-survival program through the direct or indirect regulation of critical molecules or signaling cascades [17,19]. We studied the effect of CK2 inhibition on bortezomib-induced cytotoxicity and evaluated the signaling pathways potentially counteracting bortezomib action in MM and MCL patients. We demonstrated that CK2 inhibitors cooperate with bortezomib in causing MM and MCL cell apoptosis by down modulating the signalling cascades of NF-kB and STAT3 and by potentiating the proteotoxic effects due to proteasome blockage. The data offer the rationale for the use of CK2 inhibitors in bortezomib-based combination therapies in these malignancies
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