Inhibition of protein kinase CK2 suppresses angiogenesis and hematopoietic stem cell recruitment to retinal neovascularization sites

Abstract

Ubiquitous protein kinase CK2 participates in a variety of key cellular functions. We have explored CK2 involvement in angiogenesis. As shown previously, CK2 inhibition reduced endothelial cell proliferation, survival and migration, tube formation, and secondary sprouting on Matrigel. Intraperitoneally administered CK2 inhibitors significantly reduced preretinal neovascularization in a mouse model of proliferative retinopathy. In this model, CK2 inhibitors had an additive effect with somatostatin analog, octreotide, resulting in marked dose reduction for the drug to achieve the same effect. CK2 inhibitors may thus emerge as potent future drugs aimed at inhibiting pathological angiogenesis. Immunostaining of the retina revealed predominant CK2 expression in astrocytes. In human diabetic retinas, mRNA levels of all CK2 subunits decreased, consistent with increased apoptosis. Importantly, a specific CK2 inhibitor prevented recruitment of bone marrow-derived hematopoietic stem cells to areas of retinal neovascularization. This may provide a novel mechanism of action of CK2 inhibitors on newly forming vessels.

CX-4945, an Orally Bioavailable Selective Inhibitor of Protein Kinase CK2, Inhibits Prosurvival and Angiogenic Signaling and Exhibits Antitumor Efficacy

“…CK2 has been described as a master regulator of angiogenesis (19). Indeed, chemical inhibitors of CK2 have previously been shown to inhibit proangiogenic activity in HUVEC and block retinal neovascularization in mice (19,21,47).…”

“…Indeed, chemical inhibitors of CK2 have previously been shown to inhibit proangiogenic activity in HUVEC and block retinal neovascularization in mice (19,21,47). PI3K/Akt signaling is known to regulate the response of endothelial cells to growth factor signaling including proliferation, migration, and tube formation (41), and thus represents a molecular mechanism through which CK2 may drive angiogenic signaling.…”

“…CK2 has been described as a master regulator of angiogenesis due to its role in multiple molecular events that contribute to angiogenesis (19). This includes regulation of the PI3K/Akt pathway, which has a Research.…”

“…The PI3K/Akt pathway is the most commonly altered signaling pathway in human cancers (16) and this pathway is susceptible to activation by CK2 (17,18). Furthermore, CK2 has been characterized as a "master regulator" of angiogenesis (19), an extrinsic non-oncogene-driven process. CK2 is elevated under hypoxic conditions, regulates hypoxiainducible transcription factor 1 alpha (HIF-1a) activity (20) and mediates the aberrant response of epithelial cells to growth factor signaling (21).…”

Protein Kinase CK2 and Angiogenesis

“…In a subsequent study, it was shown that bone marrow derived human stem cells injected into the vitreous of neonatal mice can incorporate into the retinal neovasculature. Administration of a CK2 inhibitor significantly reduced this incorporation [68]. Thus, beside its impact on the growth factors, CK2 may interfere with human stem cell recruitment during angiogenesis.…”