Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Title

The herbal compound cryptotanshinone restores sensitivity in cancer cells that are resistant to the tumor necrosis factor-related apoptosis-inducing ligand

Language

English

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells but not normal cells. However, TRAIL resistance due to low level of TRAIL receptor expression is widely found in cancer cells and hampers its development for cancer treatment. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are urgently needed. We investigated whether tanshinones, the major bioactive compounds of Salvia miltiorrhiza (danshen), can up-regulate TRAIL receptor expression. Among the major tanshinones being tested, cryptotanshinone (CT) showed the best ability to induce TRAIL receptor 2 (DR5) expression. We further showed that CT was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. CT-induced DR5 induction was not cell type-specific, as DR5 induction was observed in other cancer cell types. DR5 knockdown abolished the enhancing effect of CT on TRAIL responses. Mechanistically, induction of the DR5 by CT was found to be p53- independent but dependent on the induction of CCAAT/enhancer- binding protein-homologous protein (CHOP). Knockdown of CHOP abolished CT-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, CT-induced ROS production preceded up-regulation ofCHOPand DR5 and consequent sensitization of cells to TRAIL. Interestingly, CT also converted TRAIL-resistant lung A549 cancer cells into TRAIL-sensitive cells. Taken together, our results indicate thatCT can potentiate TRAIL-induced apoptosis through up-regulation of DR5. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Publication Date

2013

Source Publication Title

Journal of Biological Chemistry

Volume

288

Issue

41

Start Page

29923

End Page

29933

Publisher

American Society for Biochemistry and Molecular Biology

DOI

10.1074/jbc.M113.483909

Link to Publisher's Edition

http://dx.doi.org/10.1074/jbc.M113.483909

ISSN (print)

00219258

ISSN (electronic)

1083351X

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