Journal Article

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

Jun Hee Lim, Jong-Wook Park, Kyeong Sook Choi, Yong Bok Park and Taeg Kyu Kwon

in Carcinogenesis

Volume 30, issue 5, pages 729-736
Published in print May 2009 | ISSN: 0143-3334
Published online November 2008 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgn265
Rottlerin induces apoptosis via death receptor 5 (DR5) upregulation through CHOP-dependent and PKC δ-independent mechanism in human malignant tumor cells

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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 δ, not only suppression of PKC δ expression by siRNA but also overexpression of wild-type-PKC δ or dominant-negative-PKC δ did not affect the rottlerin-mediated induction of DR5 in our study. These results suggest that rottlerin induces upregulation of DR5 via PKC δ-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.

Journal Article.  5358 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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