Resumen de The Role of Protein Kinase CK2 in pro-survival pathways in clear cell renal cell carcinoma (ccRCC) cells
Estefania Alcaraz Muñoz
Protein kinase CK2 is a Serine/Threonine kinase widely expressed in all eukaryotic organisms. To date, more than 300 substrates for this kinase have been discovered, most of them essential for cell viability. For that reason, CK2 has been considered as a protein kinase decisive for the viability of all eukaryotic cells. CK2 plays pivotal roles in cell survival, proliferation and anti-apoptotic mechanisms, and its dysregulation is associated with human malignancies. Furthermore, the pleiotropic effects of this protein have connected CK2 with other pathways that are crucial in several processes involved in tumorigenesis. However, little is known on the potential cross-talk between CK2 and these signalling pathways in clear cell renal cell carcinoma (ccRCC) cells. The purpose of this work has been to study the involvement of CK2 in the molecular basis of ccRCC, analysing the effect of CK2 inhibition on Akt and ERK1/2 signalling pathways in response to heparin-binding EGF-like growth factor (HB-EGF), as well as the connection between CK2 and ErbB4, which has been found downregulated in ccRCC. In order to assess this goal, CK2 activity has been targeted by pharmacological inhibitors, and the regulatory and catalytic CK2 subunits have been independently silenced by short hairpin RNA (shRNA), in tubular proximal cells derived from normal kidney (HK-2), and cells derived from a primary clear cell adenocarcinoma (786-O). The most striking result is that CK2 inhibition, either by chemical inhibitors or shRNA down-regulation, impairs the activation of Akt and ERK1/2 in response to HB-EGF, which are decisive signalling pathways involved in the process of cell death, proliferation and autophagy. Likewise, down-regulation of regulatory subunit CK2ß is accompanied by changes in the expression of Epithelial-Mesenchymal-Transition (EMT) markers, such as E-cadherin and Snail1. Interestingly, the results of this study suggest that CK2ß down-regulation induces HIF-a expression and STAT3 phosphorylation which may contribute to E-cadherin and Snail1 regulation in ccRCC cells. On the other hand, overexpression of ErbB4 in 786-O cells alters cell proliferation as well as enhances HB-EGF-induced Akt and ERK1/2 activation. In addition, CK2 inhibition by CX-4945 and down-regulation of CK2ß by siRNAs results in a significant reduction of ErbB4 levels. The results of this research show that CK2 affects key components of signalling pathways, such as ErbB4, Akt, ERK1/2, HIF-a, Snail 1 and STAT3 in renal cells, supporting the potential involvement of CK2 in ccRCC.
