Multiple myeloma cell survival relies on high activity of protein kinase CK2

Abstract

Casein kinase 2 (CK2) is a ubiquitous cellular serine-threonine kinase that regulates relevant biologic processes, many of which are dysregulated in malignant plasma cells. Here we investigated its role in multiple myeloma (MM). Analysis of MM cell lines and highly purified malignant plasma cells in patients with MM revealed higher protein and CK2 activity levels than in controls (normal in vitro-generated polyclonal plasma cells and B lymphocytes). The inhibition of CK2 with specific synthetic compounds or by means of RNA interference caused a cytotoxic effect on MM plasma cells that could not be overcome by IL-6 or IGF-I and that was associated with the activation of extrinsic and intrinsic caspase cascades. CK2 blockage lowered the sensitivity threshold of MM plasma cells to the cytotoxic effect of melphalan. CK2 inhibition also resulted in impaired IL-6-dependent STAT3 activation and in decreased basal and TNF-α-dependent IκBα degradation and NF-κB-driven transcription. Our data show that CK2 was involved in the pathophysiology of MM, suggesting that it might play a crucial role in controlling survival and sensitivity to chemotherapeutics of malignant plasma cells.

Protein kinase CK2 – A key suppressor of apoptosis

“…Experimental transgenic mouse models of neoplasia in which altered CK2 signal served as a double transgene have provided significant support to this notion (e.g., Kelliher et al, 1996;Xu et al, 1999). The presence of elevated CK2 in cancer appears to correlate with the pathological status of the cancer and may serve as a prognostic marker (Yenice et al, 1994;Gapany et al, 1995;Faust et al, 1996;Faust et al, 1999;Piazza et al, 2006;Laramas et al, 2007). Although CK2 is present ubiquitously in all cells, it is noteworthy that its distribution in the normal versus cancer cells is distinct.…”

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

“…46 CK2 in MM CK2 has also been implicated in the pathogenesis of MM. 47 Our group described that CK2 is crucial for malignant plasma cell survival demonstrating that this protein kinase positively regulates STAT3 and NF-kB-dependent signaling. CK2 activity and CK2a and b protein levels were found upregulated in MM cell lines and primary cells.…”

“…Similarly, we demonstrated that CK2 inhibition caused a reduction in STAT3 phospho-Tyr705 and phospho-Ser727 levels, implying this kinase as a positive regulator of two critical pro-survival pathways in MM. 47 Moreover, CK2 could be instrumental for the modulation of MM cell sensitivity to novel therapeutic agents. A recent study has reported that CK2 could represent a central kinase downstream inhibition of the proteasome with bortezomib, thus influencing the cell phosphoproteome and many signaling pathways upon treatment with this central, widely employed therapeutic agent.…”

“…This could rely on the observation that CK2 has been shown to increase the sensitivity of these tumor cells to chemotherapeutics. 47,59 Another scenario in which CK2 inhibition could be exploited is together with first and second generation BCR-ABL inhibitors, such as imatinib, dasatinib and nilotinib. Indeed, CK2 being an important target downstream of BCR-ABL, it likely contributes in sustaining the transformed phenotype promoted by this oncogenic fusion protein.…”

Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors

“…These kinases are, to the best of our knowledge, not known to contribute to BAD phosphorylation. The alpha isoforms of Casein kinase I (CK1, CSNK1) 16 and II (CK2, CSNK2) 17 have been implicated in contributing to multiple myeloma pathology, although the relevance of CK1 and CK2 in the setting of Pim overexpression is not known. Therefore, we believe off-target kinase inhibition to be a limited risk in the interpretation of the impact of 9c on BAD phosphorylation, but activity on CK1α/ CK2α may impact the viability of KMS-12-BM.…”