Effects of CK2 Inhibition on Multiple Signaling Pathways in Myeloma Cells

Abstract

CK2 serine-threonine kinase plays a key role in promoting cell survival of multiple myeloma (MM) cells through modulation of extrinsic and intrinsic apoptotis and by activating pro-survival signaling such as the NF-κB and STAT3 pathways (Piazza FA et al. 2006, Blood 105:1698–1707). Here we deepened our previous results and placed the CK2 action inside critical pathways for MM cell growth, like the MAPK, STAT3 and Wnt regulated cascades.We employed MM cell lines, primary cells from MM patients and human cervical carcinoma cell line HeLa. Inhibition of CK2 was obtained with well characterized chemical compounds (TBB, K27 and K17) or by RNA interference.CK2 inhibition led to an increased p38 MAPK activation and to a decreased basal and growth factor stimulated-ERK1,2 phosphorylation. These changes were associated to increased activation of apoptotis and cell death. Inhibition of PP1 and PP2A phosphatases led to a decreased p38 MAPK phosphorylation upon CK2 inhibition, suggesting that CK2 may control p38 activity through the modulation of these molecules. Activation of upstream JAK tyrosine kinase upon cytokine or growth factor stimulation are a prerequisite for STAT3 activation. Following inhibition of CK2 activity, Tyk2 phosphorylation and JAK2 activation were found impaired and these effects were associated to a decreased STAT3 phosphorylation in tyr705 and ser727. In turn, activated-STAT3 nuclear migration and STAT3-dependent transcription of target genes, like the pro-survival bcl-2 family member mcl-1 and the cell-cycle promoter cyclin-D1, were significantly reduced.Finally, Wnt activation was also affected by CK2 manipulation. Indeed, β-catenin activation and transcriptional activity were impaired by the treatment of MM cells with CK2 inhibitors; these effects were associated with reduced cell proliferation and cell death.Altogether, these data demonstrate that CK2 is a key player placed at the cross-road of important signaling pathways for MM cell growth and reinforce the possibility that it may represent an ideal target molecule for therapeutic purposes.