HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity.
Bottom Line: Although scriptaid induced activation of both p38MAPK and JNK, it was the inhibition of JNK that attenuated scriptaid-induced apoptosis significantly.Scriptaid also increased the expression of (i) p21 and p27 involved in cell-cycle regulation and (ii) γH2AX associated with DNA damage response in a JNK-dependent manner.Taken together, our findings indicate that scriptaid (i) induces apoptosis and reduces glioma cell proliferation by elevating JNK activation and (ii) also decreases telomerase activity in a JNK-independent manner.
Affiliation: National Brain Research Centre, Manesar, Haryana, India.Show MeSH
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Mentions: Inhibition of tumour cell-cycle arrest through JNK activation has been reported . Because JNK activation is involved in scriptaid-induced glioma cell death, we investigated whether JNK pathway modulate cell-cycle regulatory proteins by determining p21 and p27 expression in glioma cells treated with scriptaid in the presence and absence of JNK inhibitors. The increased p21 and p27 expression observed upon scriptaid treatment was reversed in the presence of JNK inhibitor (Fig. 6). Ras induces DNA damage signalling response  and JNK activation radiosensitizes colon carcinoma cells through enhanced DNA damage . Because increased Ras and JNK activation was observed in scriptaid-treated cells, we determined the expression of γ-H2AX in cells treated with scriptaid in the presence and absence of JNK inhibitors. The elevated levels of γH2AX observed in scriptaid-treated cells were abrogated to control levels in the presence of JNK inhibitor (Fig. 7). The increase in pJNK levels observed in scriptaid-treated cells was decreased to control levels in the presence of JNK inhibitor. These results indicate the involvement of JNK in scriptaid-induced DSB response in glioma cells.
Affiliation: National Brain Research Centre, Manesar, Haryana, India.