Suppression of death receptor 5 enhances cancer cell invasion and metastasis through activation of caspase-8/TRAF2-mediated signaling.
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.
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
You-Take
YT
Oh
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Ping
P
Yue
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Dongsheng
D
Wang
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA, USA.
Jing-Shan
JS
Tong
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Zhuo G
ZG
Chen
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Fadlo R
FR
Khuri
Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Shi-Yong
SY
Sun
D000818:Animals; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D053200:Fas-Associated Death Domain Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047992:TNF Receptor-Associated Factor 2; D053181:Caspase 8; D020781:Matrix Metalloproteinase 1
TRAF2; caspase-8; death receptor 5; invasion; metastasis