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Author Notes:

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

We are grateful to Drs. K Vuori, H Habeldah, AD Sharrocks, WS El-Deiry, K Ye and L Zhang for providing antibodies, plasmids or cell lines. We are also thankful to Dr. A. Hammond in our department for editing the manuscript.

The authors declare that they have no conflict of interest.

Subjects:

Research Funding:

This study was supported by NIH/NCI SPORE P50 grant CA128613 (to S-Y Sun for Project 2), NIH/NCI cancer center P30 grant CA138292, Emory Winship Cancer Institute Robbins Scholar award (to Y-T Oh) and Emory Winship Cancer Institute Halpern Research Scholar award (to S-Y Sun)

Y-T Oh is a recipient of Emory Winship Cancer Institute Robbins Scholar award. S-Y Sun is a Halpern Research Scholar. ZG Chen, FR Khuri and S-Y Sun are Georgia Research Alliance Distinguished Cancer Scientists.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • death receptor 5
  • invasion
  • metastasis
  • caspase-8
  • TRAF2
  • APOPTOSIS-INDUCING LIGAND
  • LUNG-CANCER
  • TRAIL-R
  • TUMOR-DEVELOPMENT
  • PROGNOSTIC VALUE
  • BREAST-CANCER
  • EXPRESSION
  • MUTATIONS
  • PROGRESSION
  • PATHWAY

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

Tools:

Journal Title:

Oncotarget

Volume:

Volume 6, Number 38

Publisher:

, Pages 41324-41338

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2015 Oh et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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