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
Related in: MedlinePlus
Mentions: Telomerase is composed primarily of the catalytic subunit (hTERT) and the RNA template (hTERC), and hallmarks of telomere dysfunction include chromosome end fusion and telomere shortening, which can lead to cell-cycle arrest. Telomerase inhibition is also known to cause apoptosis in human cancers . HDAC inhibitors have been reported to suppress telomerase reverse transcriptase mRNA expression in prostate cancer cells . Besides, JNK is a key regulator of telomerase activity . Because the pro-apoptotic effects of scriptaid are partially mediated by JNK, we investigated the ability of scriptaid to effect telomerase activity in the presence and absence of JNK inhibitor. An approximate 50% reduction in telomerase activity was observed in both LN229 and T98G cells, upon treatment with 20 μM scriptaid (Fig. 8). However, scriptaid-mediated decrease in telomerase activity was not JNK mediated as telomerase activity observed in scriptaid-treated cells was unaffected in the presence of JNK inhibitor (Fig. 8). As inhibition of telomerase activity has been suggested to cause cell death in glioma , the ability of scriptaid to abrogate telomerase activity may subsequently result in reduced glioma cell proliferation and cell death.
Affiliation: National Brain Research Centre, Manesar, Haryana, India.