Enzastaurin induces H2AX phosphorylation to regulate apoptosis via MAPK signalling in malignant glioma cells.
Enzastaurin is an acyclic bisindolylmaleimide derived from staurosporine that acts as an ATP competitor, and interferes with the activity of protein kinase C (PKC) isoforms. Our previous studies have shown that clinically achievable concentrations of this agent induce apoptosis in many glioma cell lines. Our goal in this study was to expand on the previous results and to determine the signalling mechanisms responsible for enzastaurin-induced inhibition of cell growth and induction of apoptosis. To address these issues, cell cycle progression following enzastaurin treatment was analysed by fluorescence-activated cell sorting (FACS) in parallel with analyses of growth and apoptosis signalling pathways. Enzastaurin treatment activated H2AX and Chk2 phosphorylation, and enhanced phosphorylation of mitogen-activated protein kinase (MAPK) family kinases. Inhibition of MAP kinases by chemical inhibitors reduced H2AX and Chk2 phosphorylation and decreased apoptosis induced by enzastaurin. These data call attention to a novel signalling pathway (MAPK/H2AX) to regulate apoptosis in malignant glioma cells.
Jane
Esther P
EP
Department of Neurosurgery, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute Brain Tumor Center, Pittsburgh, PA 15213, USA.
Pollack
Ian F
IF
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy*; D006657:Histones / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor
D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D007211:Indoles; D050794:STAT1 Transcription Factor; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C504878:enzastaurin