title: Down-regulation of c-FLIP contributes to the sensitization effect of 3,3'-diindolylmethane on TRAIL-induced apoptosis in cancer cells.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, which has been shown to preferentially induce apoptosis in cancer cells without adverse effects on normal cells. However, there are still some cancer cells, especially those with high malignancy, resistant to TRAIL-induced apoptosis, impeding the clinical anticancer efficiency of TRAIL. In this report, we showed that 3,3'-diindolylmethane, an indole compound derived from cruciferous vegetables, is capable of overcoming TRAIL resistance by sensitizing TRAIL-induced apoptosis in human cancer cells. Noncytotoxic concentrations of 3,3'-diindolylmethane significantly enhanced TRAIL-resistant cancer cells to TRAIL-induced apoptosis via promoting the caspase cascade, a process independent of nuclear factor-kappaB activation and cell surface TRAIL receptor expression. In the search of the molecular mechanisms involved in the sensitization activity of 3,3'-diindolylmethane, we found that combined treatment of 3,3'-diindolylmethane and TRAIL led to significant down-regulation of the cellular FLICE inhibitory protein expression (c-FLIP). Furthermore, we provided evidence showing that the reduced c-FLIP level is predominately mediated by the ubiquitin-proteasome degradation system. These findings reveal a novel anticancer property of 3,3'-diindolylmethane and suggest that this compound could have potential use in cancer therapy to overcome TRAIL resistance.
authors.affiliation: Department of Community, Occupational and Family Medicine, Faculty of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Singapore.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.forename: Choon Nam
authors.initials: CN
authors.lastname: Ong
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D017931:DNA Primers; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C016392:3,3'-diindolylmethane