Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis.

Abstract

Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75NTR) and subsequent generation of the p75NTR intracellular domain (ICD) endow cancer cells with resistance to anoikis. p75NTR ICD promoted expression of TNF receptor-associated factor 6 (TRAF6), a critical intermediary in p75NTR ICD-mediated signal transduction, at the translational level. Cell detachment-induced activation of EGFR triggered autoubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NFκB, and eventually led to anoikis resistance. ADAM10 and p75NTR ICD also promoted tumor metastasis formation in vivo Together, our findings uncover a previously unknown function for the ADAM10-p75NTR ICD-TRAF6-NFκB axis in preventing anoikis and suggest ADAM10 and p75NTR ICD as potential cancer therapeutic targets.Significance: These findings identify the ADAM10-p75NTR ICD-TRAF6-NFκB signaling axis as a potential candidate for cancer therapy. Cancer Res; 78(9); 2262-76. ©2018 AACR.

• Authors: Xin Bao, Jianbo Shi, Furong Xie, Zengying Liu, Jingshuang Yu, Wantao Chen, Zhiyuan Zhang, Qin Xu
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 9 Pg. 2262-2276 (05 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29437707 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Biomarkers
• Intracellular Signaling Peptides and Proteins
• NGFR protein, human
• Nerve Tissue Proteins
• Receptors, Nerve Growth Factor
• TNF Receptor-Associated Factor 6
• Tifab protein, human
• ADAM10 Protein

Topics

• ADAM10 Protein (metabolism)
• Anoikis
• Biomarkers
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms (genetics, metabolism, pathology)
• Humans
• Intracellular Signaling Peptides and Proteins
• Neoplasm Metastasis
• Neoplasm Staging
• Nerve Tissue Proteins (chemistry, metabolism)
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Multimerization
• Proteolysis
• RNA Interference
• Receptors, Nerve Growth Factor (chemistry, metabolism)
• TNF Receptor-Associated Factor 6 (genetics, metabolism)
• Ubiquitination