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

Oncotarget. 2015 Dec 1;6(38):41324-38. doi: 10.18632/oncotarget.5847.

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.

Keywords: TRAF2; caspase-8; death receptor 5; invasion; metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Caspase 8 / metabolism*
  • Cell Line, Tumor
  • Enzyme Activation
  • Fas-Associated Death Domain Protein / metabolism
  • Female
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System*
  • Matrix Metalloproteinase 1 / metabolism
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / therapy
  • RNA Interference
  • RNAi Therapeutics / methods
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Xenograft Model Antitumor Assays / methods

Substances

  • Fas-Associated Death Domain Protein
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF Receptor-Associated Factor 2
  • Caspase 8
  • Matrix Metalloproteinase 1