Alterations in Ca2+ signaling, and c-fos and nur77 expression are associated with sodium butyrate-induced differentiation of C6 glioma cell.

Sodium butyrate is well known in stimulating growth and differentiation of cancer cells. In the present study, butyrate treatment caused decreases in thymidine incorporation in the early passages (45-60) of C6 glioma cells. In addition, butyrate also caused decreases in inositol incorporation and transient ATP-stimulated Ca2+ mobilization suggesting that butyrate altered general mechanisms of Ca2+ signaling in these cells. To gain direct insight into the crosstalk between sodium butyrate and Ca2+ signaling in transcriptional regulation, we investigated the induction of the Ca2+-sensitive immediate early genes (IEGs), c-fos, nur77 and c-myc. Sodium butyrate per se enhanced the expression of c-fos mRNA, and the enhanced levels were maintained for 24 h, but over the same time period, the initially increased levels of nur77 expression tailed off, while c-myc expression was slightly reduced. Increasing intracellular Ca2+ concentration ([Ca2+]i) by thapsgargin and A23187 induced the expression of both c-fos and nur77 mRNA expression, and synergistic effects were observed when cells were incubated with sodium butyrate plus thapsgargin and A23187. However, removal of both extracellular Ca2+ by EGTA, or intracellular free Ca2+ with BAPTA did not affect the sodium butyrate-induced c-fos and nur77 mRNA. These results suggest that although sodium butyrate altered Ca2+ signaling which is an important regulatory mechanism for c-fos and nur77 expression, nevertheless the sodium butyrate-induced c-fos and nur77 expression may be not in fact mediated through Ca2+ signaling.