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Carcinogenesis Advance Access published online on November 26, 2008
Carcinogenesis, doi:10.1093/carcin/bgn265
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Rottlerin induces apoptosis via death receptor5 (DR5) up-regulation through CHOP-dependent and PKC {delta}-independent mechanism in human malignant tumor cells

Jun Hee Lim1, Jong-Wook Park1, Kyeong Sook Choi2, Yong Bok Park3 and Taeg Kyu Kwon1,*

1 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
2 Institute for Medical Sciences, Ajou University School of Medicine, 5 Woncheon-Dong, Paldal-Gu, Suwon 442-749, South Korea
3 Department of Genetic Engineering, College of Natural Sciences, Kyungpook National University, Taegu, Korea

* Corresponding author Taeg Kyu Kwon, Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong, Jung-Gu, Taegu, 700-712, Korea. Tel.: 82-53-250-7846, Fax: 82-53-250-7074. e-mail: kwontk{at}dsmc.or.kr

Rottlerin has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. In this study, we demonstrate a novel mechanism of rottlerin-induced apoptosis via death receptor 5 (DR5) up-regulation. We found that treatment with rottlerin significantly induces DR5 expression both at its mRNA and protein levels. Down-regulation of DR5 expression with siRNA efficiently attenuated rottlerin-induced apoptosis, showing that the critical role of DR5 in this cell death. Rottlerin-induced DR5 up-regulation 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 {delta}, not only suppression of PKC {delta} expression by siRNA but also overexpression of WT-PKC {delta} or DN-PKC {delta} did not affect the rottlerin-mediated induction of DR5 in our study. These results suggest that rottlerin induces up-regulation of DR5 via PKC {delta}-independent pathway. Furthermore, subtoxic dose of rottlerin sensitizes human cancer cells, but not normal cells, to 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.

Key Words: Rottlerin • DR5 • Apoptosis • PKC {delta} • CHOP

Received June 25, 2008; revised October 23, 2008; accepted November 20, 2008.


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