Oncotarget

Research Papers:

Carnosic acid sensitized TRAILmediated apoptosis through downregulation of cFLIP and Bcl2 expression at the post translational levels and CHOPdependent upregulation of DR5 Bim and PUMA expression in human carcinoma caki cells

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Oncotarget. 2015; 6:1556-1568. https://doi.org/10.18632/oncotarget.2727

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Kyong-Jin Jung1,*, Kyoung-jin Min1,*, Jae Hoon Bae2, Taeg Kyu Kwon1

1Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, South Korea

2Department of Physiology, School of Medicine, Keimyung University, Daegu 704-701, South Korea

*These authors have contributed equally to this work

Correspondence to:

Taeg Kyu Kwon, e-mail: [email protected]

Keywords: Carnosic acid, TRAIL, Bcl-2, c-FLIP, CHOP

Received: September 19, 2014     Accepted: November 08, 2014     Published: January 22, 2015

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.