Proteolytic release of the p75NTR intracellular domain by ADAM10 promotes metastasis and resistance to anoikis

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) endows 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 epidermal growth factor receptor (EGFR) triggered auto-ubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NF-κB, 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-NF-κB axis in preventing anoikis and suggest ADAM10 and p75NTR ICD as potential cancer therapeutic targets.

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