Carcinogenesis Advance Access originally published online on November 26, 2008
Carcinogenesis 2009 30(5):729-736; doi:10.1093/carcin/bgn265
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Rottlerin induces apoptosis via death receptor 5 (DR5) upregulation through CHOP-dependent and PKC 
-independent mechanism in human malignant tumor cells
Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea
1 Department of Molecular Science and Technology, Institute for Medical Sciences, Ajou University School of Medicine, 5 Woncheon-Dong, Paldal-Gu, Suwon 442-749, South Korea
2 Department of Genetic Engineering, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Korea
* To whom correspondence should be addressed. Tel: +82 53 250 7846; Fax: +82 53 250 7074; Email: kwontk{at}dsmc.or.kr
Rottlerin has been shown to induce antiproliferation and apoptosis of human cancer cell lines. In this study, we demonstrate a novel mechanism of rottlerin-induced apoptosis via death receptor (DR) 5 upregulation. We found that treatment with rottlerin significantly induces DR5 expression both at its messenger RNA and protein levels. Downregulation of DR5 expression with small-interfering RNA (siRNA) efficiently attenuated rottlerin-induced apoptosis, showing that the critical role of DR5 in this cell death. Rottlerin-induced DR5 upregulation was accompanied by CCAAT/enhancer-binding protein–homologous protein (CHOP) protein expression and rottlerin-induced increase of DR5 promoter activity was diminished by mutation of a CHOP-binding site of DR5 promoter. Although rottlerin is known to be as an inhibitor of novel isoforms of protein kinase C (PKC), specifically PKC 
, not only suppression of PKC expression by siRNA but also overexpression of wild-type-PKC or dominant-negative-PKC did not affect the rottlerin-mediated induction of DR5 in our study. These results suggest that rottlerin induces upregulation of DR5 via PKC -independent pathway. Furthermore, subtoxic dose of rottlerin sensitizes human cancer cells, but not normal cells, to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Thus, DR5-mediated apoptosis, which is induced by rottlerin alone or by the combined treatment with rottlerin and TRAIL, may offer a new therapeutic strategy against cancer.
Abbreviations: CHOP, CCAAT/enhancer-binding protein–homologous protein; DN, dominant negative; DR, death receptor; GFP, green fluorescent protein; HSC70, heat shock cognate protein 70; mRNA, messenger RNA; PARP, poly(ADP-ribose) polymerase; PCR, polymerase chain reaction; PKC, protein kinase C; ROS, reactive oxygen species; RT, reverse transcriptase; siRNA, small-interfering RNA; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; WT, wild-type
Received June 25, 2008; revised October 23, 2008; accepted November 20, 2008.
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