The XIAP inhibitor Embelin enhances TRAIL-induced apoptosis in human leukemia cells by DR4 and DR5 upregulation
- 266 Downloads
The present study was designed to explore the effects of low-toxicity Embelin on TRAIL-induced apoptosis and its possible mechanism in human leukemia cells. Our study showed that low-toxicity Embelin enhanced TRAIL-induced apoptosis through DR4 and DR5 upregulation and caspase activation in HL-60 cells. Pan-caspase inhibitor Z-VAD-FMK inhibited cell apoptosis induced by TRAIL alone or combined with low-toxicity Embelin, which indicated the cytotoxic effect is mediated by caspase-dependent apoptosis. Although Embelin is an X chromosome-linked inhibitor-of-apoptosis protein (XIAP) inhibitor, an XIAP independent effect on cell death was detected in HL-60 cells exposed to low-toxicity Embelin and TRAIL. Low-toxicity Embelin upregulated DR4 and DR5 expression to enhance TRAIL-induced apoptosis. The sensitizing effects of Embelin on TRAIL-induced apoptosis were markedly attenuated when DR4/DR5 was knocked down. These data suggested that low-toxicity Embelin enhanced TRAIL-induced cell apoptosis through DR4 and DR5 upregulation, indicating that combination of low-toxicity Embelin and TRAIL may become as a potential antileukemia strategy.
KeywordsTRAIL Death receptor XIAP Leukemia Apoptosis
Conflicts of interest
- 2.Schneider P, Olson D, Tardivel A, Browning B, Lugovskoy A, Gong D, et al. Identification of a new murine tumor necrosis factor receptor locus that contains two novel murine receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J Biol Chem. 2003;278:5444–54.CrossRefPubMedGoogle Scholar
- 10.Ahn KS, Sethi G, Aggarwal BB. Embelin, an inhibitor of X chromosome-linked inhibitor-of- apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic geneproducts. Mol Pharmacol. 2007;71:209–19.CrossRefPubMedGoogle Scholar
- 25.Zou W, Liu X, Yue P, Zhou Z, Sporn MB, Lotan R, et al. C-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res. 2004;64:7570–8.CrossRefPubMedGoogle Scholar