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  • Many studies have also demonstrated that CK inhibition profo

    2019-11-04

    Many studies have also demonstrated that CK2 inhibition profoundly affects the PI3K/AKT pathway in different cancer models; promising results have been obtained in hematological malignancies (Buontempo et al., 2014, Borgo et al., 2013, Piazza et al., 2012, Cheong et al., 2010, Gowda et al., 2016), as well as in prostate (Ryu et al., 2012, Chatterjee et al., 2013, Pierre et al., 2011), breast (Noh et al., 2011, Gray et al., 2014), lung (Stahl et al., 2011, Bliesath et al., 2012, Ku et al., 2013, So et al., 2015), head and neck cancer (Bian et al., 2015), hepatocellular carcinoma (Zhang et al., 2015), and glioblastoma (Kang et al., 2017) among others. The opposing model could also be anticipated, whereby AKT inhibition impacts CK2 signaling leading to a therapeutic response (Nguyen and Mitchell, 2013). Given the cooperation of CK2 and AKT in promoting survival signaling, another prediction is that combined targeting of both kinases could produce a more pronounced and durable response in blocking cancer cell survival and progression. A synergistic response has indeed been observed through association of CK2 and PI3K/AKT inhibitors (Cheong et al., 2010; Guerra, 2006). However, isoform-specific differences between AKT isoforms and their regulation by CK2 warns against oversimplified conclusions on the opportunity of targeting these two kinases as a general approach in cancer therapy. It is therefore mandatory that this complex functional interplay is taken into account when devising therapies based on their targeting, in order to potentiate, rather than mitigate, drug efficacy.
    Conflicts of interest
    Funding statement The work performed in our laboratory was supported in part by grants from Associazione Italiana per la Ricerca sul Cancro [AIRC, grant IG 14180], Istituto Superiore di Sanità (ISS oncoproteome network prot. 2011-527TR1) and Fondazione Cassa di Risparmio Vignola 2015 to SM ([email protected]@FCRVMARM2015).
    Acknowledgement
    Introduction CK2 kinases are ubiquitous highly conserved GDC-0834 protein kinases (PKs) that have roles in various essential and pathological biological processes.1, 2, 3, 4, 5, 6, 7 In mammals the CK2 serine/threonine kinase family is composed of 2 enzymes, CK2α and CK2α’. CK2 kinases can function as monomeric kinases and within a tetrameric complex. The latter is composed of two CK2 catalytic units (CK2α and/or CK2α’) and two regulatory units (CK2β). In many types of cancer CK2 is overexpressed, it favors rapid proliferation and survival of cancer cells and supports angiogenesis.8, 9, 10, 11, 12, 13, 14, 15 In turn, pharmacological inhibition or downregulation of CK2 by gene silencing has been shown to suppress angiogenesis and induce apoptosis.10, 16, 17, 18, 19, 20, 21 Within the past decade, two inhibitors of CK2-catalyzed protein phosphorylation, CX-4945 (Silmitasertib) and CIGB-300, entered clinical trials (www.clinicaltrials.gov identifiers: NCT02128282 and NCT01639625), both as anticancer agents. CX-4945 is an ATP-competitive CK2 inhibitor, whereas CIGB-300 is a peptidic inhibitor of CK2-catalyzed reaction that binds to the phospho-acceptor domain of CK2 substrates, thus impairing the correct phosphorylation by the enzyme. In addition, the overexpression of CK2 often correlates with the diagnosis of cancer, suggesting that the PK is not only a potential drug target but may also serve as a biomarker for certain types of malignancy.8, 11, 12, 18, 22 The implication of CK2 in malaria, neurodegenerative and several other human diseases23, 24, 25 has been described that increases the pharmacological potential of inhibition of CK2. A large number of inhibitors of CK2 has been developed. Most of them are rigid small molecules that contain one or more aromatic carbo- or heterocycles; these compounds target the ATP-binding pocket of the enzyme. CK2 is an acidophilic PK that has the preference to phosphorylate serine/threonine residues in negatively charged regions of proteins. Accordingly, CK2 is also inhibited by negatively charged oligomers such as heparin28, 29 and bisubstrate inhibitors comprising an anionic peptide or peptoid fragment.30, 31, 32, 33 The activity of CK2 and inhibitory potential of compounds towards CK2 have been mostly assessed by monitoring the CK2-catalyzed phosphorylation of synthetic peptide substrates with radioactively labeled GDC-0834 ATP, the handling of which requires special precautions. Therefore, photoluminescence-based binding and displacement assays could be valuable alternatives for quantification of catalytically active PKs and for screening and characterization of inhibitors.30, 34