Histone deacetylase (HDAC) inhibitors have been elucidated to induce hyperacetylation of histones resulting in transcriptionally active chromatin structure. Recently, inhibition of HDAC has represented a new strategy in human cancer therapy, since HDAC inhibitors induce growth arrest and apoptosis in some carcinoma cell lines. Adenosine-signaling has been shown to possess antiapoptotic properties through its receptor, e.g.,
the activation of A2A
receptor by the A2A
receptor agonist CGS21680 protects PC12 cells from oxidative stress-induced apoptosis. In this study, we tested the biological effect of the HDAC inhibitor trichostatin A (TSA) on PC12 cells, and found that treatment with TSA resulted in a significant decrease of the viability of PC12 cells in dose- and time-dependent manners. The cell death features revealed apoptosis accompanied by nuclear condensation and chromosomal DNA fragmentation. Western blot analysis showed that hyperacetylation of histone H3 occurred 6-10 hr after addition of TSA in PC12 cells. Accordingly, the phosphorylation of JNK was observed in a similar time course. 100 nM CGS21680 showed a counter effect on TSA-induced PC12 cell death when it was added 5-7 hr after addition of TSA. CGS21680 increased the survival signals, such as the phosphorylation of ERK1/2 and Akt, in PC12 cells. The protective effect of CGS21680 was inhibited by the A2A
selective antagonist CSC. Taken together, A2A
adenosine receptors are involved in the control of survival of PC12 cells and may contribute to regulation of cellular viability in response to epigenetic modulation.
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