Casein kinase 2 inhibition attenuates cholesterol oxidation product-induced apoptosis by suppressing the activation of the mitochondrial pathway and the caspase-8- and bid-dependent pathways

Abstract

Protein casein kinase 2 is involved in signal transduction, cell growth and apoptosis. However, it is unclear whether the cholesterol oxidation product-induced cell death is regulated by casein kinase 2. Therefore, in the respect of the cell death process, we assessed the regulatory effect of the casein kinase 2 on the cholesterol oxidation product-induced apoptosis in neuronal cells using differentiated PC12 cells. Casein kinase 2 inhibitors (4,5,6,7-tetrabromobezotriazole (TBB) and apigenin) which do not have toxic effects, reduced the 7-ketocholesterol or 25-hydroxycholesterol-induced cell death and nuclear damage in PC12 cells. Treatment with TBB inhibited the 7-ketocholesterol-induced decrease in Bid, Bcl-2 and survivin protein levels, increase in Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3), cleavage of PARP-1, and increase in the tumor suppressor p53 levels. The results showed that the casein kinase 2 inhibitor at the concentrations tested which does not induce toxic effects, may attenuate the cholesterol oxidation product-induced apoptosis in differentiated PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect appears to be ascribed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH.