Role of protein kinase CK2 in antitumor drug resistance

Abstract

Drug resistance represents the major reason of pharmacological treatment failure. It is supported by a broad spectrum of mechanisms, whose molecular bases have been frequently correlated to aberrant protein phosphorylation. CK2 is a constitutively active protein kinase which phosphorylates hundreds of substrates; it is expressed in all cells, but its level is commonly found higher in cancer cells, where it plays anti-apoptotic, pro-migration and pro-proliferation functions. Several evidences support a role for CK2 in processes directly responsible of drug resistance, such as drug efflux and DNA repair; moreover, CK2 intervenes in signaling pathways which are crucial to evade drug response (as PI3K/AKT/PTEN, NF-κB, β-catenin, hedgehog signaling, p53), and controls the activity of chaperone machineries fundamental in resistant cells. Interestingly, a panel of specific and effective inhibitors of CK2 is available, and several examples are known of their efficacy in resistant cells, with synergistic effect when used in combination with conventional drugs, also in vivo. Here we analyze and discuss evidences supporting the hypothesis that CK2 targeting represents a valuable strategy to overcome drug resistance.

Keywords: Antitumor agents; CK2; CKII; Casein kinase 2; DNA repair; Drug resistance; Protein kinase inhibitors.

Fig. 1

CK2-dependent control of drug efflux through actions on the MDR pumps

Fig. 2

Mechanisms of CK2 control on cellular responses to DNA damage in chemo-resistant cells

Fig. 3

CK2 actions on chaperone machinery (a), NF-κB signaling (b), and PI3K/AKT/PTEN pathway (c). Phosphorylation causes substrate inhibition if indicate in red, activation if indicated in green

Fig. 4

Summary of mechanisms of drug resistance potentiated by CK2 (left side, red), and corresponding effect of CK2 inhibition (right side, green)