Protein kinase CK2 is a regulator of angiogenesis in endometriotic lesions

Abstract

Endometriosis is a frequent gynecological disease, which is crucially dependent on the process of angiogenesis. However, the underlying regulatory mechanisms of blood vessel development are still poorly understood. CK2 is a pleiotropic protein kinase, which is implicated in the regulation of various cellular processes including angiogenesis. Herein we studied for the first time the function of protein kinase CK2 in angiogenesis of endometriotic lesions. For this purpose, we analyzed the anti-angiogenic activity of the CK2 inhibitor quinalizarin in a rat aortic ring assay and its effect on the expression of individual CK2 subunits and on kinase activity in endometrial tissue. Moreover, endometriotic lesions were induced in dorsal skinfold chambers of quinalizarin- and vehicle-treated C57BL/6 mice to study their vascularization and morphology by means of repetitive intravital fluorescence microscopy and histology. Our results demonstrate that quinalizarin dose-dependently inhibits vascular sprouting. In addition, treatment of endometrial tissue with quinalizarin reduces CK2 activity without affecting the expression of the three CK2 subunits α, α' and β. In the dorsal skinfold chamber model of endometriosis, quinalizarin inhibits the vascularization of endometriotic lesions, which exhibit a significantly decreased vascularized area and functional capillary density when compared to those of vehicle-treated controls. This is associated with a reduced lesion size and histological fraction of endometrial glands. These findings indicate that CK2 is a regulator of angiogenesis in endometriotic lesions. Accordingly, inhibition of CK2 represents a novel option in the development of anti-angiogenic strategies for the treatment of endometriosis.

Inhibition of protein kinase CK2 suppresses tumor necrosis factor (TNF)-α-induced leukocyte–endothelial cell interaction

“…In contrast, quinalizarin exhibits a binding affinity of Ki = 0.052 μM [38], which is comparable to that of other commonly used CK2 inhibitors, such as 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), tetrabromocinnamic acid (TBCA) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBB) [44][45][46]. Quinalizarin and CX-4945 have previously been shown to effectively reduce the activity of CK2 in animal studies focusing on cancer [40,42] and endometriosis [19]. Moreover, CX-4945 has even successfully entered phase II clinical trials [47].…”

“…The consensus sequence contains serine or threonine residues surrounded by acidic amino acids [17]. This kinase is involved in various cellular processes, including proliferation, differentiation, apoptosis and angiogenesis [18][19][20][21]. However, the specific function of CK2 on leukocyte-endothelial cell interaction during TNF-α-induced inflammation remains elusive.…”

Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice

“…SRPIN803 inhibited not only SRPK1 but also CK2, an important regulator of hypoxia-inducible factor-1 activity that activates transcription of VEGF gene (Mottet et al, 2005). Inhibitors of CK2 decrease VEGF production in retinal pigmental epithelial cells (Mottet et al, 2005;Pollreisz et al, 2013), suppress proliferation and migration of retinal endothelial cells (Ljubimov et al, 2004), and decrease retinal neovascularization in mouse models of oxygen-induced retinopathy (Kramerov et al, 2008) and endometriotic lesions (Feng et al, 2012). Furthermore, siRNA-mediated knockdown of CK2 decreased VEGF mRNA expression and VEGF protein level.…”

Protein Kinase CK2 and Angiogenesis

“…Endometriosis is a frequent gynaecological disease, which depends crucially on angiogenesis, supplying endometriotic lesions with oxygen and nutrients. It was recently shown that inhibition of the CK2 kinase activity suppresses vascularization of developing endometriotic lesions [42]. Blood vessel formation in endometriotic lesions is a complex process which is driven by angiogenic growth factors such as the vascular endothelial growth factor (VEGF), the fibroblast growth factor (FGF) and the platelet derived growth factor (PDGF).…”