title: Lipoxygenase inhibitors induce death receptor 5/TRAIL-R2 expression and sensitize malignant tumor cells to TRAIL-induced apoptosis.
abstract: Lipoxygenases induce malignant tumor progression and lipoxygenase inhibitors have been considered as promising anti-tumor agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. Combined treatment with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, and TRAIL markedly induced apoptosis in Jurkat T-cell leukemia cells at suboptimal concentrations for each agent. The combined treatment efficiently activated caspase-3, -8 and -10, and Bid. The underling mechanism by which NDGA enhanced TRAIL-induced apoptosis was examined. NDGA did not change the expression levels of anti-apoptotic factors, Bcl-x(L), Bcl-2, cIAP-1, XIAP and survivin. The expression of death receptor-related genes was investigated and it was found that NDGA specifically up-regulated the expression of death receptor 5 (DR5) at mRNA and protein levels. Down-regulation of DR5 by small interfering RNA prevented the sensitizing effect of NDGA on TRAIL-induced apoptosis. Furthermore, NDGA sensitized prostate cancer and colorectal cancer cells to TRAIL-induced apoptosis. In contrast, NDGA neither enhanced TRAIL-induced apoptosis nor up-regulated DR5 expression in normal peripheral blood mononuclear cells. Another lipoxygenase inhibitor, AA861, also up-regulated DR5 and sensitized Jurkat and DU145 cells to TRAIL. These results indicate that lipoxygenase inhibitors augment the apoptotic efficiency of TRAIL through DR5 up-regulation in malignant tumor cells, and raise the possibility that the combination of lipoxygenase inhibitor and TRAIL is a promising strategy for malignant tumor treatment.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Takumi
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Mano
authors.initials: M
authors.lastname: Horinaka
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakata
authors.forename: Takashi
authors.initials: T
authors.lastname: Yasuda
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Goda
authors.forename: Miki
authors.initials: M
authors.lastname: Wakada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizutani
authors.forename: Tsuneharu
authors.initials: T
authors.lastname: Miki
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009637:Masoprocol / Q000494:pharmacology; D050506:Mutant Chimeric Proteins / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D007141:Immunoglobulin Fc Fragments; D016859:Lipoxygenase Inhibitors; D050506:Mutant Chimeric Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D009637:Masoprocol; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone