Oncotarget

Research Papers:

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

Kyong-Jin Jung _, Kyoung-Jin Min, Jae Hoon Bae and Taeg Kyu Kwon

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

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Abstract

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: kwontk@dsmc.or.kr

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.


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