HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity.
The present study identified a novel mechanism of induction of apoptosis in glioblastoma cells by scriptaid - a histone deacetylase (HDAC) inhibitor. Scriptaid reduced glioma cell viability by increasing Jun N-terminal kinase (JNK) activation. 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. Treatment with scriptaid increased Ras activity in glioma cells, and transfection of cells with constitutively active RasV12 further sensitized glioma cells to scriptaid-induced apoptosis. Scriptaid also inhibited telomerase activity independent of JNK. 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.
Sharma
Vivek
V
National Brain Research Centre, Manesar, Haryana, India.
Koul
Nitin
N
Joseph
Christy
C
Dixit
Deobrat
D
Ghosh
Sadashib
S
Sen
Ellora
E
D000107:Acetylation / Q000187:drug effects; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D000873:Anthracenes; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006898:Hydroxylamines; D011804:Quinolines; C410733:scriptaid; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D019098:Telomerase; D006655:Histone Deacetylases; D018631:ras Proteins