title: 6-Shogaol enhances renal carcinoma Caki cells to TRAIL-induced apoptosis through reactive oxygen species-mediated cytochrome c release and down-regulation of c-FLIP(L) expression.
abstract: 6-Shogaol, a potent bioactive compound in ginger (Zingiber officinale Roscoe), has been reported for anti-inflammatory and anti-cancer activity. In this study, we investigated the effect of 6-shogaol to enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The combined treatment with 6-shogaol and TRAIL markedly induces apoptosis in various cancer cells (renal carcinoma Caki cells, breast carcinoma MDA-MB-231 cells and glioma U118MG cells), but not in normal mesangial cells and normal mouse kidney cells. 6-Shogaol reduced the mitochondrial membrane potential (MMP) and released cytochrome c from mitochondria to cytosol via Bax activation. Furthermore, we found that 6-shogaol induced down-regulation of c-FLIP(L) expression at the post-translational levels and the overexpression of c-FLIP(L) markedly inhibited 6-shogaol plus TRAIL-induced apoptosis. Moreover, 6-shogaol increased reactive oxygen species (ROS) production in Caki cells. Pretreatment with ROS scavengers attenuated 6-shogaol plus TRAIL-induced apoptosis through inhibition of MMP reduction and down-regulation of c-FLIP(L) expression. In addition, 6-gingerol, another phenolic alkanone isolated from ginger, did not enhance TRAIL-induced apoptosis and down-regulate c-FLIP(L) expression. Taken together, our results demonstrated that 6-shogaol enhances TRAIL-mediated apoptosis in renal carcinoma Caki cells via ROS-mediated cytochrome c release and down-regulation of c-FLIP(L) expression.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Min Ae
authors.initials: MA
authors.lastname: Han
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Seon Min
authors.initials: SM
authors.lastname: Woo
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Kyoung-jin
authors.initials: KJ
authors.lastname: Min
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Shin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Jong-Wook
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Otolaryngology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
authors.forename: Dong Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: Deaprtment of Pharmacology, School of Medicine, Kyungpook National University, Daegu, South Korea.
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, South Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea. Electronic address: kwontk@dsmc.or.kr.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002396:Catechols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002396:Catechols; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C040115:shogaol; D045304:Cytochromes c
keywords: 6-Shogaol; Apoptosis; ROS; TRAIL; c-FLIP(L)