Oncotarget

Research Papers:

Selenocysteine derivative overcomes TRAIL resistance in melanoma cells: evidence for ROS-dependent synergism and signaling crosstalk

Wenqiang Cao, Xiaoling Li, Shanyuan Zheng, Wenjie Zheng, Yum-shing Wong and Tianfeng Chen _

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Oncotarget. 2014; 5:7431-7445. https://doi.org/10.18632/oncotarget.2008

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Abstract

Wenqiang Cao1, Xiaoling Li1, Shanyuan Zheng2, Wenjie Zheng1, Yum-shing Wong2 and Tianfeng Chen1

1 Department of Chemistry, Jinan University, Guangzhou, China.

2 School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong S.A.R., China

Correspondence:

Tianfeng Chen, email:

Wenjie Zheng, email:

Keywords: Chemosensitizer; TRAIL; Selenium; apoptosis; ROS; p53

Received: April 11, 2014 Accepted: May 24, 2014 Published: May 26, 2014

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), as one of the most promising targeted drug for new cancer therapeutics, is limited in clinical application by the evolution of resistance in many cancer cell lines, especially in malignant melanoma. Thus, it is urgently needed to identify chemosensitizers to enhance the apoptotic inducing efficacy of TRAIL and overcome resistance of malignant melanoma cells. Herein, we reported that 3,3′-diselenodipropionic acid (DSeA), a Selenocysteine derivative, could synergistically enhance the growth inhibitory effect of TRAIL on A375 melanoma cells though induction of ROS-dependent apoptosis with involvement of PTEN-mediated Akt inactivation and DNA damage-mediated p53 phosphorylation, which subsequently activated mitochondrial and death receptor apoptotic pathways. Moreover, silencing of p53 down-regulated the expression levels of p53-inducible genes, and effectively blocked the cell apoptosis. Suppression of PI3K significantly increased the apoptotic cell death. In contrast, antioxidants effectively reversed the cell apoptosis through regulation of Akt and p53 signaling pathways. Taken together, the combination of DSeA and TRAIL could be a novel strategy to overcome TRAIL resistance in malignant melanoma, and DSeA may be candidates for further evaluation as a chemosensitizer in clinical trails.


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