The XIAP inhibitor Embelin enhances TRAIL-mediated apoptosis in malignant glioma cells by down-regulation of the short isoform of FLIP

M D Siegelin, Timo Gaiser, Y Siegelin
Neurochemistry International 2009, 55 (6): 423-30
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.

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