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Highly pleiotropic and constitutively active protein kinase CK2 is a key target in cancer therapy, but only one small-molecule inhibitor has reached clinical trials—CX-4945. In this study, we present the indeno[1,2-b]indole derivative 5-isopropyl-4-methoxy-7-methyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (5a-2) that decreased the intracellular CK2 activity in A431, A549, and LNCaP tumor cell lines analogous to CX-4945 (> 75% inhibition at 20 µm) and similarly blocked CK2-specific Akt phosphorylation in LNCaP cells. Cellular uptake analysis demonstrated higher intracellular concentrations of 5a-2 (408.3 nm) compared with CX-4945 (119.3 nm). This finding clarifies the comparable effects of both compounds on the intracellular CK2 activity despite their different inhibitory potency in vitro [IC50 = 25 nm (5a-2) and 3.7 nm (CX-4945)]. Examination of the effects of both CK2 inhibitors on cancer cells using live-cell imaging revealed notable differences. Whereas CX-4945 showed a stronger pro-apoptotic effect on tumor cells, 5a-2 was more effective in inhibiting tumor cell migration. Our results showed that 49% of intracellular CX-4945 was localized in the nuclear fraction, whereas 71% of 5a-2 was detectable in the cytoplasm. The different subcellular distribution, and thus the site of CK2 inhibition, provides a possible explanation for the different cellular effects. Our study indicates that investigating CK2 inhibition-mediated cellular effects in relation to the subcellular sites of CK2 inhibition may help to improve our understanding of the preferential roles of CK2 within different cancer cell compartments., Finanziert über die DEAL-Vereinbarung mit Wiley 2019-2022.

The regulation of insulin biosynthesis and secretion in pancreatic β-cells is essential for glucose homeostasis in humans. Previous findings point to the highly conserved, ubiquitously expressed serine/threonine kinase CK2 as having a negative regulatory impact on this regulation. In the cell culture model of rat pancreatic β-cells INS-1, insulin secretion is enhanced after CK2 inhibition. This enhancement is preceded by a rise in the cytosolic Ca2+ concentration. Here, we identified the serine residues S2362 and S2364 of the voltage-dependent calcium channel CaV2.1 as targets of CK2 phosphorylation. Furthermore, co-immunoprecipitation experiments revealed that CaV2.1 binds to CK2 in vitro and in vivo. CaV2.1 knockdown experiments showed that the increase in the intracellular Ca2+ concentration, followed by an enhanced insulin secretion upon CK2 inhibition, is due to a Ca2+ influx through CaV2.1 channels. In summary, our results point to a modulating role of CK2 in the CaV2.1-mediated exocytosis of insulin.

Since diabetes is a global epidemic, the development of novel therapeutic strategies for the treatment of this disease is of major clinical interest. Diabetes is differentiated in two types: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM arises from an autoimmune destruction of insulin-producing β-cells whereas T2DM is characterized by an insulin resistance, an impaired insulin reaction of the target cells, and/or dysregulated insulin secretion. In the past, a growing number of studies have reported on the important role of the protein kinase CK2 in the regulation of the survival and endocrine function of pancreatic β-cells. In fact, inhibition of CK2 is capable of reducing cytokine-induced loss of β-cells and increases insulin expression as well as secretion by various pathways that are regulated by reversible phosphorylation of proteins. Moreover, CK2 inhibition modulates pathways that are involved in the development of diabetes and prevents signal transduction, leading to late complications such as diabetic retinopathy. Hence, targeting CK2 may represent a novel therapeutic strategy for the treatment of diabetes.

Hintergrund: Zeitdruck, emotionale Anforderungen und Fachkräftemangel aufgrund der demografischen Entwicklung führen zu psychischen Belastungen bei Pflegenden in Langzeitpflegeeinrichtungen. Häufig wird Burnout in Zusammenhang mit Pflegekräften gebracht. Es liegen den Pflegeeinrichtungen je nach Bundesland unterschiedliche Pflegepersonalbedarfsberechnungen für Langzeitpflegeeinrichtungen zu Grunde. Einen signifikanten Unterschied in der Berechnung des Pflegepersonals weisen die Pflegeeinrichtungen in Wien und Niederösterreich auf. Das Ziel dieser Arbeit ist, die psychosozialen Faktoren zu quantifizieren und herauszuarbeiten, welchen Einfluss der Personalschlüssel darauf hat. Methode: In einer Stichprobenziehung fand eine Fragebogenerhebung mit einem standardisierten Fragenbogen bei Pflegekräften (n=117) statt. Sie wurde in von privaten Trägern geführten Einrichtungen, davon vier Pflegeheimen in Wien und acht Langzeitpflegeeinrichtungen in Niederösterreich, durchgeführt. Die Auswertung erfolgte über Statistical Package for Social Scientist (SPSS) 25. Ergebnisse: Psychische Belastungen, bedingt durch Arbeitsbedingungen, sind bei allen Berufsgruppen, die in der Pflege beschäftigt sind vorzufinden. Es zeigt sich, dass die niederösterreichischen Pflegekräfte in Bezug auf Vorgesetzte, Arbeitsbedingungen, Privat-Arbeit-Konflikte, Zufriedenheit, Verbundenheit mit dem Arbeitsplatz, physischen und psychischen Anforderungen weniger belastet sind als das Pflegepersonal in Wien. Schlussfolgerungen: Zeitdruck, körperliche, psychische und emotionale Anforderungen zählen zu den häufigsten psychischen Belastungen der Pflegenden in Langzeitpflegeeinrichtungen. Jedoch stellen Führungskräfte eine wichtige Ressource für die Mitarbeiterinnen und Mitarbeiter zur Bewältigung von psychischen Belastungen dar. Im Sinne der Verbesserung von Arbeitsbedingungen und zur Sicherung der Pflegequalität wäre eine einheitliche Personalbedarfsrechnung in Österreichs Langzeitpflegeeinrichtungen wünschenswert. Background: Time pressure, emotional demands and shortage of skilled caregivers due to demographic development lead to psychological stress among nursing staff in long-term care facilities. Burnout is often associated with nursing staff. Depending on the federal states, the nursing facilities are based on different calculations of nursing staff requirements for long-term care facilities. The nursing facilities in Vienna and Lower Austria show a significant difference in the calculation of nursing staff. The aim of this study was to quantify the psychosocial factors and the influence of the personnel key on them. Methods: A survey with a standardised questionnaire for nursing staff (n=117) was carried out in a sample drawing. It took place in institutions, including four nursing homes in Vienna and eight long-term care institutions in Lower Austria all run by private institutions. The evaluation was conducted via Statistical Package for Social Scientist (SPSS) 25. Results: Psychological stress, caused by working conditions, can be found in all occupational groups employed in nursing. It can be seen that the Lower Austrian nursing staff are less burdened than the nursing staff in Vienna with regard to supervisors, working conditions, work-privacy-conflicts, work contentedness, attachment to the workplace, physical and psychological demands. Conclusions: Time pressure, physical, psychological and emotional demands are among the most frequent psychological burdens on caregivers in long-term care facilities. However, managers represent an important resource for the staff to cope with psychological stress. In order to improve working conditions and ensure the quality of care, a consistent personnel requirement calculation in Austria's long-term care facilities would be desirable. vorgelegt von: Claudia Götz Wien, FH Campus Wien, Masterarb., 2019