Contribution of the CK2 Catalytic Isoforms α and α’ to the Glycolytic Phenotype of Tumor Cells

Abstract

CK2 is a Ser/Thr protein kinase overexpressed in many cancers. It is usually present in cells as a tetrameric enzyme, composed of two catalytic (α or α’) and two regulatory (β) subunits, but it is active also in its monomeric form, and the specific role of the different isoforms is largely unknown. CK2 phosphorylates several substrates related to the uncontrolled proliferation, motility, and survival of cancer cells. As a consequence, tumor cells are addicted to CK2, relying on its activity more than healthy cells for their life, and exploiting it for developing multiple oncological hallmarks. However, little is known about CK2 contribution to the metabolic rewiring of cancer cells. With this study we aimed at shedding some light on it, especially focusing on the CK2 role in the glycolytic onco-phenotype. By analyzing neuroblastoma and osteosarcoma cell lines depleted of either one (α) or the other (α’) CK2 catalytic subunit, we also aimed at disclosing possible pro-tumor functions which are specific of a CK2 isoform. Our results suggest that both CK2 α and α’ contribute to cell proliferation, survival and tumorigenicity. The analyzed metabolic features disclosed a role of CK2 in tumor metabolism, and suggest prominent functions for CK2 α isoform. Results were also confirmed by CK2 pharmacological inhibition. Overall, our study provides new information on the mechanism of cancer cells addiction to CK2 and on its isoform-specific functions, with fundamental implications for improving future therapeutic strategies based on CK2 targeting.

CIGB-300-Regulated Proteome Reveals Common and Tailored Response Patterns of AML Cells to CK2 Inhibition

“…This highly pleiotropic Ser/Thr kinase is responsible for roughly 25% of cellular phosphoproteome, thus playing instrumental roles in normal and pathological states ( Meggio and Pinna, 2003 ; Borgo et al, 2021 ). Of note, CK2 stands among the most studied kinases in recent years, and its contribution to the malignant phenotype and cancer progression has been suggested by mounting pieces of evidence ( Trembley et al, 2009 ; Chua et al, 2017 ; Zonta et al, 2021 ). In particular, CK2 modulates signaling pathways critical for hematopoietic cell survival and function, and its high expression and activity in acute myeloid leukemia (AML) have been associated with worse prognosis and reduced overall survival ( Kim et al, 2007 ; Quotti Tubi et al, 2017 ).…”

Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors

“…CK2 is involved in the regulation of many cellular processes including cell growth, proliferation and death. The protein is often overexpressed in cancer cells and some become addicted to CK2 activity 35 , 36 . As a result, CK2 has emerged as an interesting target in oncology but very few molecules (for example, CX-4945) have made it to clinical trials so far.…”

Protein Kinase CK2α’, More than a Backup of CK2α

“…Salizzato et al have analyzed the influence of the deletion of individual CK2 subunits on myogenic differentiation [103]. CK2α KO C2C12 myoblast cells exhibit a substantial down-regulation of CK2β, as also shown by [104]; whereas, CK2α' KO cells showed very similar levels of CK2α and CK2β to the control cells. The differentiation program of CK2α' KO cells is similar to the control cells.…”