Chimeric peptides as modulators of CK2-dependent signaling: Mechanism of action and off-target effects.
Protein kinase CK2 is a tetrameric enzyme composed of two catalytic (α/α') and two regulatory (β) subunits. It has a global prosurvival function, especially in cancer, and represents an attractive therapeutic target. Most CK2 inhibitors available so far are ATP-competitive compounds; however, the possibility to block only the phosphorylation of few substrates has been recently explored, and a compound composed of a Tat cell-penetrating peptide and an active cyclic peptide, selected for its ability to bind to the CK2 substrate E7 protein of human papilloma virus, has been developed [Perea et al., Cancer Res. 2004; 64:7127-7129]. By using a similar chimeric peptide (CK2 modulatory chimeric peptide, CK2-MCP), we performed a study to dissect its molecular mechanism of action and the signaling pathways that it affects in cells. We found that it directly interacts with CK2 itself, counteracting the regulatory and stabilizing functions of the β subunit. Cell treatment with CK2-MCP induces a rapid decrease of the amount of CK2 subunits, as well as of other signaling proteins. Concomitant cell death is observed, more pronounced in tumor cells and not accompanied by apoptotic events. CK2 relocalizes to lysosomes, whose proteases are activated, while the proteasome machinery is inhibited. Several sequence variants of the chimeric peptide have been also synthesized, and their effects compared to those of the parental peptide. Intriguingly, the Tat moiety is essential not only for cell penetration but also for the in vitro efficacy of the peptide. We conclude that this class of chimeric peptides, in addition to altering some properties of CK2 holoenzyme, affects several other cellular targets, causing profound perturbations of cell biology. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Sofia
S
Zanin
CRIBI Biotechnology Centre, University of Padova, Padova, Italy.
Michele
M
Sandre
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Giorgio
G
Cozza
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Daniele
D
Ottaviani
Department of Biomedical Sciences, University of Padova, Padova, Italy; CRIBI Biotechnology Centre, University of Padova, Padova, Italy. Electronic address: oriano.marin@unipd.it.
Oriano
O
Marin
Department of Biomedical Sciences, University of Padova, Padova, Italy; CNR Institute of Neurosciences, Padova, Italy.
Lorenzo A
LA
Pinna
Department of Biomedical Sciences, University of Padova, Padova, Italy. Electronic address: maria.ruzzene@unipd.it.
Maria
M
Ruzzene
D000595:Amino Acid Sequence; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity
D057846:Cell-Penetrating Peptides; D050725:Papillomavirus E7 Proteins; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II
CIGB-300; CK2; CKII; Casein kinase; Chimeric peptides; Inhibitors