Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis
| Autor: | Jianbo Shi, Zengying Liu, Jingshuang Yu, Furong Xie, Wantao Chen, Xin Bao, Zhiyuan Zhang, Qin Xu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Cell growth Chemistry ADAM10 Cell medicine.disease Metastasis 03 medical and health sciences 030104 developmental biology medicine.anatomical_structure Oncology Cancer cell Cancer research medicine Anoikis Tumor necrosis factor alpha sense organs Signal transduction |
| Zdroj: | Cancer Research. 78:2262-2276 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-17-2789 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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