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  • In the course of carbohydrate metabolism pyruvate the end pr


    In the course of carbohydrate metabolism, pyruvate, the end product of glycolysis, is converted to acetyl-CoA, which fuels the citrate cycle for further generation of energy. In the case of elevated levels of acetyl-CoA, acetyl-CoA is converted into malonyl-CoA by the action of acetyl-CoA carboxylase (Fig. 2). Malonyl-CoA is the starting molecule for the synthesis of fatty-acids. It is known for a long time that cytosolic fatty acyl-CoA esters are responsible for glucose induced insulin secretion [47]. The acetyl-CoA carboxylase expression is regulated by binding of the transcription factor Sp1 to one of the promoter elements of acetyl-CoA carboxylase. It was shown that SP1 was phosphorylated by CK2 and moreover, that CK2 phosphorylation of SP1 led to an inactivation of SP1 binding to the promoter element [48] of acetyl-CoA carboxylase (Fig. 2). These results suggest that the phosphorylation of SP1 by CK2 is implicated in the regulation of glucose mediated insulin secretion in pancreatic β-cells. It was further shown that insulin activates CK2 for the phosphorylation of acetyl-CoA carboxylase [49]. Glycerol-3-phosphate acyltransferase (mtGAT), which resides in the mitochondrial outer membrane, catalyzes the first step in de novo glycerolipid biosynthesis to produce lysophosphatidic acid. It was shown that CK2 phosphorylates mtGAT and this phosphorylation results in an increased GAT activity [50], [51]. Both enzymes, acetyl-CoA-carboxylase and glycerol-3-phosphate acyltransferase are stimulated by insulin [52], [53]. Starvation, decreases and refeeding a high carbohydrate diet, increases both acetyl-CoA-carboxylase and glycerol-3-phosphate acetyltransferase. Both enzymes however, show a decreased activity as a result of exercise. The role of CK2 in the regulation of carbohydrate metabolism was also shown in animal models. The Km value for casein of CK2 from diabetic rats was about 2 fold lower than that from control animals. Interestingly, insulin treatment of diabetic rats increased the Km for casein of CK2 [23]. These alterations for the Km value promoted by diabetes on CK2 were not restricted to casein as a substrate but were also found for HMG14 protein and for glycogen synthase. CK2 activity from a diabetic rat liver cytosol was significantly higher than that from control rats when casein was used as the substrate. The amounts of CK2 were not altered. The Km values for glycogen synthase, casein and phosvitin were significantly reduced in diabetic as opposed to control rats [23].
    Clinical and therapeutical implications A direct link of CK2 to energy metabolism of the cell is provided by the fact that CK2 activity and protein level are elevated under hypoxic conditions. It regulates the hypoxia inducible transcription factor 1 alpha (HIF-1α) activity [54]. Due to the generalized elevated activity of CK2 in rapidly proliferating K-Ras(G12C) inhibitor 12 sale and its central role in multiple signalling pathways and in the regulation of metabolic pathways, there are numerous efforts to develop selective CK2 inhibitors. One ATP competitive inhibitor of the catalytic CK2α and CK2α’ subunits, namely CX-4945 is orally bio-available and now in clinical phase I trial [55], [56]. This inhibitor targets the enzyme itself, however, in another approach, a peptide which targets the acidic phosphoacceptor site on CK2 substrates was used to neutralize CK2 [57]. This peptide called CIGB-300 is now also in clinical phase I trial [58]. Yet, as shown in this review, not only does CK2 have an impact on the hormonal regulation of metabolic pathways, but also on enzymes in these pathways. It also seems that CK2 itself can be regulated by insulin and glucose. Due to these very different effects in cells the use of CK2 inhibitors in patients must therefore be treated with great caution.
    Conflict of interest
    Introduction Casein kinase II (CK2) and Glycogen Synthase Kinase-3 (GSK-3) are two ubiquitous, highly expressed serine/threonine kinases that are involved in the regulation of multiple pathways (Pinna, 1994, Woodgett, 1990). Over the last several decades, tremendous advances have been made in understanding the biochemical and biological functions of these proteins in physiological and pathological conditions. Although these studies produced a wealth of knowledge and provided novel insights into a number of physiological processes, there are many unanswered questions regarding the roles of these enzymes in health and disease. More recently, the development of inhibitors for these kinases provided the opportunity to modify their activity as a therapeutic strategy for various diseases. Since both CK2 and GSK-3 regulate pathways that are essential for cellular proliferation, it is not surprising that inhibitors of these enzymes were tested first as potential therapeutic agents for malignant diseases. The initial success of these inhibitors in preclinical studies further enhanced interest in the function of CK2 and GSK-3 in regulating cellular proliferation. The recent discovery of a novel CK2-Ikaros signaling axis and its role in the regulation of the phosphatidylinositol 3-kinase (PI3K) pathway in leukemia (Song et al., 2015), along with the known role of GSK-3 in regulating the function of key proteins in PI3K pathway (Al-Khouri et al., 2005, Cordier et al., 2012, Maccario et al., 2007, McCubrey et al., 2015), shed new light on the role of CK2 and GSK-3 in cellular proliferation in leukemia. The purpose of this review is to briefly summarize current knowledge of the function of CK2 and GSK-3, and to highlight several interactions between CK2 and GSK-3-regulated signaling pathways that are relevant for malignant diseases with an emphasis on novel discoveries regarding the role of the CK2-Ikaros axis and GSK-3 in regulating the PI3K pathway in leukemia.