Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis
Proteolytic Release of the p75NTR Intracellular Domain by ADAM10 Promotes Metastasis and Resistance to Anoikis
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ADAM10 蛋白水解释放 p75(NTR) 胞内结构域促进转移和失巢凋亡抵抗
DOI：
10.1158/0008-5472.can-17-2789
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发表时间：
2018-05-01
期刊：
影响因子：
11.2
通讯作者：
Xu, Qin
中科院分区：
文献类型：
--
作者：
Bao, Xin;Shi, Jianbo;Xu, Qin
对失巢凋亡的抵抗使癌细胞在体循环中存活;然而，失巢凋亡抵抗的机制仍不清楚。在这里，我们表明，A解整合素和金属蛋白酶10（ADAM 10）介导的切割p75神经营养因子受体（p75（NTR））和随后产生的p75（NTR）胞内结构域（ICD）赋予癌细胞抗失巢凋亡。p75（NTR）ICD在翻译水平促进TNF受体相关因子6（TRAF 6）的表达，TRAF 6是p75（NTR）ICD介导的信号转导的关键中间体。细胞凋亡诱导的EGFR激活通过促进TRAF 6的二聚化而触发TRAF 6的自泛素化，随后激活NF κ B B，并最终导致失巢凋亡抵抗。ADAM 10和p75（NTR）ICD在体内也促进肿瘤转移形成。总之，我们的研究结果揭示了一个以前未知的功能，为ADAM 10-p75（NTR）ICD-TRAF 6-NF κ B轴在防止失巢凋亡，并建议ADAM 10和p75（NTR）ICD作为潜在的癌症治疗targets.Significance：这些研究结果确定了ADAM 10-p75（NTR）ICD-TRAF 6-NF κ B信号传导轴作为一个潜在的候选人为癌症治疗。(C)2018年AACR。
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 (p75(NTR)) and subsequent generation of the p75(NTR) intracellular domain (ICD) endow cancer cells with resistance to anoikis. p75(NTR) ICD promoted expression of TNF receptor-associated factor 6 (TRAF6), a critical intermediary in p75(NTR) ICD-mediated signal transduction, at the translational level. Cell detachment-induced activation of EGFR triggered autoubiquitination of TRAF6 by facilitating its dimerization, subsequently activated NF kappa B, and eventually led to anoikis resistance. ADAM10 and p75(NTR) ICD also promoted tumor metastasis formation in vivo. Together, our findings uncover a previously unknown function for the ADAM10-p75(NTR) ICD-TRAF6-NF kappa B axis in preventing anoikis and suggest ADAM10 and p75(NTR) ICD as potential cancer therapeutic targets.Significance: These findings identify the ADAM10-p75(NTR) ICD-TRAF6-NF kappa B signaling axis as a potential candidate for cancer therapy. (C) 2018 AACR.