It is frequently upregulated in human cancers ( Guerra and Issinger, 1999), and transgenic expression of CK2 α in lymphocytes is oncogenic ( Seldin and Leder, 1995) and accelerates leukemia development induced by other oncogenes ( Kelliher et al., 1996). CK2 phosphorylates a huge number of protein substrates, involved in many fundamental cell processes ( Meggio and Pinna, 2003), and is essential for cell life. However, at present no evidence of a dynamic regulation operated by the β-subunit in vivo has been provided, where CK2 is usually found in its holoenzymatic α 2 β 2 form, whose spontaneous dissociation under physiological conditions remains a matter of conjecture ( Filhol et al., 2004). In vitro, the recombinant catalytic subunits are active either alone or combined with the β subunits, whose presence however alters the protein substrate specificity and confers susceptibility to polybasic effectors, notably polyamines and histones ( Pinna, 1990). CK2 has a heterotetrameric structure, composed of two catalytic ( α and/or α′) and two regulatory ( β) subunits. We therefore conclude that inhibition of CK2 can be considered as a promising tool to revert the MDR phenotype.ĬK2 is an ubiquitous, highly conserved and pleiotropic Ser/Thr kinase, endowed with constitutive activity, independent of any known second messenger or phosphorylation events ( Pinna, 2002). CK2 blockade was also effective in inducing cell death of a different MDR line (U2OS). CK2 inhibitors could promote an increased uptake of chemotherapeutic drugs inside the cells and sensitize them to drug-induced apoptosis in a co-operative manner. Pharmacological downregulation of CK2 activity by a panel of specific inhibitors, or knockdown of CK2 α expression by RNA interference, were able to induce cell death in R-CEM. We found that, while the CK2 regulatory subunit β was equally expressed in the two cell variants, CK2 α catalytic subunit was higher in R-CEM and this was accompanied by a higher phosphorylation of endogenous protein substrates. We investigated its possible involvement in the multidrug resistance phenotype (MDR) by analysing its level in two variants of CEM cells, namely S-CEM and R-CEM, normally sensitive or resistant to chemical apoptosis, respectively. Protein kinase CK2 is an ubiquitous and constitutively active kinase, which phosphorylates many cellular proteins and is implicated in the regulation of cell survival, proliferation and transformation.
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