title: Gambogic acid induces apoptosis and sensitizes TRAIL-mediated apoptosis through downregulation of cFLIPL in renal carcinoma Caki cells.
abstract: Gambogic acid (GA) is a natural compound derived from brownish gamboge resin that shows a range of bioactivity, such as antitumor and antimicrobial properties. Although, GA is already known to induce cell death in a variety of cancer cells, the molecular basis for GA-induced cell death in renal cancer cells is unclear. In this study, a treatment with GA induced cell death in human renal carcinoma Caki cells in a dose-dependent manner. Treatment of Caki cells with GA decreased the levels of antiapoptotic proteins, such as Bcl-2 and XIAP in a dose-dependent manner. In addition, GA decreased the expression of the cFLIPL protein, which was downregulated at the transcriptional level without any change in the levels of cFLIPs expression. z-VAD (pan-caspase inhibitor) partially blocked GA-mediated cell death. GA-induced apoptotic cell death in Caki cells is mediated partly by the AIF translocation from the mitochondria into the nucleus via a caspase-independent pathway. In contrast, N-acetylcysteine (NAC), a ROS scavenger, had no effect on GA-induced cell death. The restoration of cFLIPL attenuated GA-induced cell death in Caki cells. Furthermore, a sub-toxic dose of GA sensitized TRAIL-mediated apoptosis in Caki cells. Pretreatment with z-VAD completely blocked GA plus TRAIL-mediated apoptosis. On the contrary, pretreatment with NAC partially inhibited GA plus TRAIL-induced apoptosis. Our findings suggested that GA induces apoptosis via the downregulation of cFLIPL and sensitized TRAIL-mediated apoptosis in Caki cells.
authors.affiliation: Department of Anatomy, College of Medicine, Yeungnam University, Nam-gu, Daegu 705-717, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Anatomy, College of Medicine, Yeungnam University, Nam-gu, Daegu 705-717, Republic of Korea.
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anatomy, College of Medicine, Yeungnam University, Nam-gu, Daegu 705-717, Republic of Korea.
authors.forename: Eon-Gi
authors.initials: EG
authors.lastname: Sung
authors.affiliation: Department of Anatomy, College of Medicine, Yeungnam University, Nam-gu, Daegu 705-717, Republic of Korea.
authors.forename: Eun-Ae
authors.initials: EA
authors.lastname: Kim
authors.affiliation: Department of Anatomy, College of Medicine, Yeungnam University, Nam-gu, Daegu 705-717, Republic of Korea.
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Lee
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D044004:Xanthones / Q000008:administration & dosage*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D044004:Xanthones; C052659:gambogic acid; D000111:Acetylcysteine