The ceramide kinase inhibitor NVP-231 inhibits breast and lung cancer cell proliferation by inducing M phase arrest and subsequent cell death

Background and Purpose Ceramide kinase (CerK) catalyzes the generation of ceramide-1-phosphate which may regulate various cellular functions, including inflammatory reactions and cell growth. Here, we studied the effect of a recently developed CerK inhibitor, NVP-231, on cancer cell proliferation and viability and investigated the role of cell cycle regulators implicated in these responses. Experimental Approach The breast and lung cancer cell lines MCF-7 and NCI-H358 were treated with increasing concentrations of NVP-231 and DNA synthesis, colony formation and cell death were determined. Flow cytometry was performed to analyse cell cycle distribution of cells and Western blot analysis was used to detect changes in cell cycle regulator expression and activation. Key Results In both cell lines, NVP-231 concentration-dependently reduced cell viability, DNA synthesis and colony formation. Moreover it induced apoptosis, as measured by increased DNA fragmentation and caspase-3 and caspase-9 cleavage. Cell cycle analysis revealed that NVP-231 decreased the number of cells in S phase and induced M phase arrest with an increased mitotic index, as determined by increased histone H3 phosphorylation. The effect on the cell cycle was even more pronounced when NVP-231 treatment was combined with staurosporine. Finally, overexpression of CerK protected, whereas down-regulation of CerK with siRNA sensitized, cells for staurosporine-induced apoptosis. Conclusions and Implications Our data demonstrate for the first time a crucial role for CerK in the M phase control in cancer cells and suggest its targeted inhibition, using drugs such as NVP-231, in combination with conventional pro-apoptotic chemotherapy.

Influence of the sunspot cycle on the Northern Hemisphere wintertime circulation from long upper-air data sets

Here we present a study of the 11 yr sunspot cycle's imprint on the Northern Hemisphere atmospheric circulation, using three recently developed gridded upper-air data sets that extend back to the early twentieth century. We find a robust response of the tropospheric late-wintertime circulation to the sunspot cycle, independent from the data set. This response is particularly significant over Europe, although results show that it is not directly related to a North Atlantic Oscillation (NAO) modulation; instead, it reveals a significant connection to the more meridional Eurasian pattern (EU). The magnitude of mean seasonal temperature changes over the European land areas locally exceeds 1 K in the lower troposphere over a sunspot cycle. We also analyse surface data to address the question whether the solar signal over Europe is temporally stable for a longer 250 yr period. The results increase our confidence in the existence of an influence of the 11 yr cycle on the European climate, but the signal is much weaker in the first half of the period compared to the second half. The last solar minimum (2005 to 2010), which was not included in our analysis, shows anomalies that are consistent with our statistical results for earlier solar minima.