Oncotarget

Research Papers:

Suppression of death receptor 5 enhances cancer cell invasion and metastasis through activation of caspase-8/TRAF2-mediated signaling

You-Take Oh _, Ping Yue, Dongsheng Wang, Jing-Shan Tong, Zhuo G. Chen, Fadlo R. Khuri and Shi-Yong Sun

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Oncotarget. 2015; 6:41324-41338. https://doi.org/10.18632/oncotarget.5847

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Abstract

You-Take Oh1, Ping Yue1, Dongsheng Wang1, Jing-Shan Tong2, Zhuo G. Chen1, Fadlo R. Khuri1, Shi-Yong Sun1

1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA

2Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA, USA

Correspondence to:

Shi-Yong Sun, e-mail: ssun@emory.edu

Keywords: death receptor 5, invasion, metastasis, caspase-8, TRAF2

Received: September 16, 2015     Accepted: September 22, 2015     Published: October 15, 2015

ABSTRACT

The role of death receptor 5 (DR5), a well-known cell surface pro-apoptotic protein, in the negative regulation of invasion and metastasis of human cancer cells and the underlying mechanisms are largely unknown and were hence the focus of this study. In this report, we have demonstrated that DR5 functions to suppress invasion and metastasis of human cancer cells, as evidenced by enhanced cancer cell invasion and metastasis upon genetic suppression of DR5 either by gene knockdown or knockout. When DR5 is suppressed, FADD and caspase-8 may recruit and stabilize TRAF2 to form a metastasis and invasion signaling complex, resulting in activation of ERK and JNK/AP-1 signaling that mediate the elevation and activation of matrix metalloproteinase-1 (MMP1) and eventual promotion of cancer invasion and metastasis. Our findings thus highlight a novel non-apoptotic function of DR5 as a suppressor of human cancer cell invasion and metastasis and suggest a basic working model elucidating the underlying biology.


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