The XIAP inhibitor Embelin enhances TRAIL-mediated apoptosis in malignant glioma cells by down-regulation of the short isoform of FLIP.
Embelin has been reported to exhibit therapeutic activity in cancer. In this study glioblastoma cells and human astrocytes were treated with Embelin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Treatment with subtoxic doses of Embelin broadly sensitized malignant glioma cells to TRAIL-mediated apoptosis. Notably, human astrocytes were not significantly affected by the combined treatment consisting of Embelin and TRAIL. Combined treatment with Embelin and TRAIL augmented the activation of initiator caspases-8/-9 and effector caspases-3/-7, respectively. Furthermore, Embelin down-regulated the expression of the long- and short-isoform of c-FLIP. In addition, forced expression of the short isoform of c-FLIP (S) attenuated apoptosis induced by the combination of Embelin and TRAIL. Embelin did not modulate the mRNA levels of c-FLIP (S), suggesting that Embelin modulates the expression of c-FLIP in a posttranscriptional manner. In summary, the short isoform of c-FLIP is a key regulator in TRAIL-Embelin-mediated apoptosis in malignant glioma.
Siegelin
M D
MD
Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany. msiegelin@t-online.de
Gaiser
Timo
T
Siegelin
Y
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D020033:Protein Isoforms; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C010945:embelin