Icariside II overcomes TRAIL resistance of melanoma cells through ROS-mediated downregulation of STAT3/cFLIP signaling

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, many melanoma cells show weak responses to TRAIL. Here, we investigated whether Icariside II (IS), an active component of Herba Epimedii, could potentiate antitumor effects of TRAIL in melanoma c...

Full description

Saved in:
Bibliographic Details
Published in:Oncotarget 2016-08, Vol.7 (32), p.52218-52229
Main Authors: Du, Juan, Wu, Jinfeng, Fu, Xiuqiong, Tse, Anfernee Kai-Wing, Li, Ting, Su, Tao, Yu, Zhi-Ling
Format: Article
Language:English
Subjects:
Antineoplastic Combined Chemotherapy Protocols - pharmacology
CASP8 and FADD-Like Apoptosis Regulating Protein - drug effects
CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism
Cell Line, Tumor
Down-Regulation
Drug Resistance, Neoplasm - drug effects
Flavonoids - pharmacology
Humans
Melanoma
Reactive Oxygen Species
Research Paper
Signal Transduction - drug effects
STAT3 Transcription Factor - drug effects
STAT3 Transcription Factor - metabolism
TNF-Related Apoptosis-Inducing Ligand - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, many melanoma cells show weak responses to TRAIL. Here, we investigated whether Icariside II (IS), an active component of Herba Epimedii, could potentiate antitumor effects of TRAIL in melanoma cells. Melanoma cells were treated with IS and/or TRAIL and cell death, apoptosis and signal transduction were analyzed. We showed that IS promoted TRAIL-induced cell death and apoptosis in A375 melanoma cells. Mechanistically, IS reduced the expression levels of cFLIP in a phospho-STAT3 (pSTAT3)-dependent manner. Ectopic expression of STAT3 abolished IS-induced cFLIP down-regulation and the associated potentiation of TRAIL-mediated cell death. Moreover, IS-induced reactive oxygen species (ROS) production preceded down-regulation of pSTAT3/cFLIP via activating AKT, and the consequent sensitization of cells to TRAIL. We also found that IS treatment down-regulated cFLIP via ROS-mediated NF-κB pathway. In addition, IS converted TRAIL-resistant melanoma MeWo and SK-MEL-28 cells into TRAIL-sensitive cells. Taken together, our results indicated that IS potentiated TRAIL-induced apoptosis through ROS-mediated down-regulation of STAT3/cFLIP signaling.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.10582