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Rottlerin induces apoptosis via death receptor 5 (DR5) upregulation through CHOP-dependent and PKC delta-independent mechanism in human malignant tumor cells.

Authors
Lim, JH; Park, JW; Choi, KS; Park, YB; Kwon, TK
Citation
Carcinogenesis, 30(5):729-736, 2009
Journal Title
Carcinogenesis
ISSN
0143-33341460-2180
Abstract
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.
MeSH terms
Acetophenones/pharmacology*Apoptosis/drug effects*Benzopyrans/pharmacology*Cell LineCell Line, TumorDNA PrimersEnzyme Inhibitors/pharmacology*Flow CytometryGenes, ReporterGlomerular Mesangium/cytologyHumansPromoter Regions, Genetic/drug effectsProtein Kinase C-delta/genetics*RNA, Small Interfering/geneticsReceptors, TNF-Related Apoptosis-Inducing Ligand/drug effectsReceptors, TNF-Related Apoptosis-Inducing Ligand/genetics*Reverse Transcriptase Polymerase Chain ReactionTranscription Factor CHOP/physiology*TransfectionUp-Regulation
DOI
10.1093/carcin/bgn265
PMID
19037087
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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