6-Shogaol enhances renal carcinoma Caki cells to TRAIL-induced apoptosis through reactive oxygen species-mediated cytochrome c release and down-regulation of c-FLIP(L) expression.

Abstract

6-Shogaol, a potent bioactive compound in ginger (Zingiber officinale Roscoe), has been reported for anti-inflammatory and anti-cancer activity. In this study, we investigated the effect of 6-shogaol to enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The combined treatment with 6-shogaol and TRAIL markedly induces apoptosis in various cancer cells (renal carcinoma Caki cells, breast carcinoma MDA-MB-231 cells and glioma U118MG cells), but not in normal mesangial cells and normal mouse kidney cells. 6-Shogaol reduced the mitochondrial membrane potential (MMP) and released cytochrome c from mitochondria to cytosol via Bax activation. Furthermore, we found that 6-shogaol induced down-regulation of c-FLIP(L) expression at the post-translational levels and the overexpression of c-FLIP(L) markedly inhibited 6-shogaol plus TRAIL-induced apoptosis. Moreover, 6-shogaol increased reactive oxygen species (ROS) production in Caki cells. Pretreatment with ROS scavengers attenuated 6-shogaol plus TRAIL-induced apoptosis through inhibition of MMP reduction and down-regulation of c-FLIP(L) expression. In addition, 6-gingerol, another phenolic alkanone isolated from ginger, did not enhance TRAIL-induced apoptosis and down-regulate c-FLIP(L) expression. Taken together, our results demonstrated that 6-shogaol enhances TRAIL-mediated apoptosis in renal carcinoma Caki cells via ROS-mediated cytochrome c release and down-regulation of c-FLIP(L) expression.

• Authors: Min Ae Han, Seon Min Woo, Kyoung-jin Min, Shin Kim, Jong-Wook Park, Dong Eun Kim, Sang Hyun Kim, Yung Hyun Choi, Taeg Kyu Kwon
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 228 Pg. 69-78 (Feb 25 2015) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 25619640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Catechols
• Reactive Oxygen Species
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• shogaol
• Cytochromes c

Topics

• Animals
• Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology)
• Apoptosis (drug effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein (deficiency, genetics, metabolism)
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Catechols (chemistry, isolation & purification, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytochromes c (metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Reactive Oxygen Species (metabolism)
• Structure-Activity Relationship
• TNF-Related Apoptosis-Inducing Ligand (metabolism)