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.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors (DR4 and DR5) and non-apoptosis-inducing decoy receptors (DcR1 and DcR2)
We investigated whether carnosic acid could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells
To further determine the molecular mechanisms underlying carnosic acid-mediated TRAIL sensitization, we investigated apoptosis-related proteins expression, including anti-apoptotic Bcl-2 family (Bcl-2, Bcl-xL, and Mcl-1), pro-apoptotic Bcl-2 family (Bim and p53 up-regulated modulator of apoptosis (PUMA)), inhibitor of apoptosis (IAP) family (XIAP and cIAP2), constituents of DISC [cellular FLICE-inhibitory protein (c-FLIP)], and death receptors (DR5)
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors (DR4 and DR5) and non-apoptosis-inducing decoy receptors (DcR1 and DcR2). TRAIL induces apoptosis in various cancer cells but has no effect in the majority of normal cells, which is supported by the presence of large numbers of death receptors (DR4 and DR5) on cancer cells [1]. Many cancer cells have resistance to TRAIL-mediated apoptosis. A number of studies reported the mechanisms of TRAIL resistance in cancer cells. Down-regulation of death receptors (DR4 and DR5) is related with TRAIL resistance. Expression of anti-apoptotic proteins, including c-FLIP, the anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and the inhibitor of apoptosis proteins (IAPs) were up-regulated. Strategy of combination treatment to overcome TRAIL resistance is needed
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