Research Papers:

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

Juan Du _, Jinfeng Wu, Xiuqiong Fu, Anfernee Kai-Wing Tse, Ting Li, Tao Su and Zhi-ling Yu

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Oncotarget. 2016; 7:52218-52229. https://doi.org/10.18632/oncotarget.10582

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Juan Du1,2,*, Jinfeng Wu1,3,*, Xiuqiong Fu1, Anfernee Kai-Wing Tse1, Ting Li1, Tao Su1, Zhi-Ling Yu1

1Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong

2Department of Chinese Medicine, Changhai Hospital, The Second Military Medicine University, Shanghai, China

3Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Zhi-Ling Yu, email: [email protected]

Keywords: melanoma, TRAIL, Icariside II, pSTAT3, ROS

Received: March 04, 2016     Accepted: June 30, 2016     Published: July 13, 2016


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.

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