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: Kyong-Jin Jung, Kyoung-jin Min, Jae Hoon Bae, Taeg Kyu Kwon
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 3 Pg. 1556-68 (Jan 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25596735 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Abietanes
• Apoptosis Regulatory Proteins
• BBC3 protein, human
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• CASP8 and FADD-Like Apoptosis Regulating Protein
• DDIT3 protein, human
• Membrane Proteins
• Plant Extracts
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Transcription Factor CHOP
• salvin

Topics

• Abietanes (administration & dosage, pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis Regulatory Proteins (biosynthesis)
• Bcl-2-Like Protein 11
• Breast Neoplasms (drug therapy, metabolism, pathology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (biosynthesis)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Drug Synergism
• Female
• Humans
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Membrane Proteins (biosynthesis)
• Mice
• Neoplasms (drug therapy, metabolism)
• Plant Extracts (administration & dosage, pharmacology)
• Proto-Oncogene Proteins (biosynthesis)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, pharmacology)
• Transcription Factor CHOP (metabolism)
• Up-Regulation (drug effects)