期刊
CARCINOGENESIS
卷 30, 期 5, 页码 729-736出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgn265
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资金
- KOSEF [M1075604000107N560400110]
- MRC at Keimyung University [R13-2002-028-01002-0]
- Korean Government (MOEHRD) [KRF-2007-355-C00050]
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 delta, not only suppression of PKC delta expression by siRNA but also overexpression of wild-type-PKC delta or dominant-negative-PKC delta did not affect the rottlerin-mediated induction of DR5 in our study. These results suggest that rottlerin induces upregulation of DR5 via PKC delta-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.
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