title: Carnosic acid sensitized TRAIL-mediated apoptosis through down-regulation of c-FLIP and Bcl-2 expression at the post translational levels and CHOP-dependent up-regulation of DR5, Bim, and PUMA expression in human carcinoma caki cells.
abstract: Carnosic acid is a phenolic diterpene from rosmarinus officinalis, and has multiple functions, such as anti-inflammatory, anti-viral, and anti-tumor activity. In this study, we examined whether carnosic acid could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that carnosic acid markedly induced TRAIL-mediated apoptosis in human renal carcinoma (Caki, ACHN, and A498), and human hepatocellular carcinoma (SK-HEP-1), and human breast carcinoma (MDA-MB-231) cells, but not normal cells (TMCK-1 and HSF). Carnosic acid induced down-regulation of c-FLIP and Bcl-2 expression at the post-translational levels, and the over-expression of c-FLIP and Bcl-2 markedly blocked carnosic acid-induced TRAIL sensitization. Furthermore, carnosic acid induced death receptor (DR)5, Bcl-2 interacting mediator of cell death (Bim), and p53 up-regulated modulator of apoptosis (PUMA) expression at the transcriptional levels via CCAAT/enhancer-binding protein-homologous protein (CHOP). Down-regulation of CHOP expression by siRNA inhibited DR5, Bim, and PUMA expression, and attenuated carnosic acid plus TRAIL-induced apoptosis. Taken together, our study demonstrates that carnosic acid enhances sensitization against TRAIL-mediated apoptosis through the down-regulation of c-FLIP and Bcl-2 expression, and up-regulation of ER stress-mediated DR5, Bim, and PUMA expression at the transcriptional levels.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Kyong-Jin
authors.initials: KJ
authors.lastname: Jung
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Kyoung-jin
authors.initials: KJ
authors.lastname: Min
authors.affiliation: Department of Physiology, School of Medicine, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Bae
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, South Korea.
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D045784:Abietanes / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D045784:Abietanes; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C497249:DDIT3 protein, human; D008565:Membrane Proteins; D010936:Plant Extracts; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051742:Transcription Factor CHOP; C018381:salvin