CD271 (NGFR) is a neurotrophin receptor that belongs to the tumor necrosis receptor (TNFR) family. Upon ligand binding, CD271 can mediate either survival or cell death. Although the role of CD271 as a marker of tumor-initiating cells is still a matter of debate, its role in melanoma progression has been well documented. Moreover, CD271 has been shown to be upregulated after exposure to both chemotherapy and targeted therapy. In this study, we demonstrate that activation of CD271 by a short β-amyloid–derived peptide (Aβ(25–35)) in combination with either chemotherapy or MAPK inhibitors induces apoptosis in 2D and 3D cultures of eight melanoma cell lines. This combinatorial treatment significantly reduced metastasis in a zebrafish xenograft model and led to significantly decreased tumor volume in mice. Administration of Aβ(25–35) in ex vivo tumors from immunotherapy- and targeted therapy–resistant patients significantly reduced proliferation of melanoma cells, showing that activation of CD271 can overcome drug resistance. Aβ(25–35) was specific to CD271-expressing cells and induced CD271 cleavage and phosphorylation of JNK (pJNK). The direct protein–protein interaction of pJNK with CD271 led to PARP1 cleavage, p53 and caspase activation, and pJNK-dependent cell death. Aβ(25–35) also mediated mitochondrial reactive oxygen species (mROS) accumulation, which induced CD271 overexpression. Finally, CD271 upregulation inhibited mROS production, revealing the presence of a negative feedback loop in mROS regulation. These results indicate that targeting CD271 can activate cell death pathways to inhibit melanoma progression and potentially overcome resistance to targeted therapy. Significance: The discovery of a means to specifically activate the CD271 death domain reveals unknown pathways mediated by the receptor and highlights new treatment possibilities for melanoma.

中文翻译：

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CD271 细胞内结构域的特异性激活与化疗或靶向治疗相结合可抑制黑色素瘤进展

CD271 (NGFR) 是一种神经营养蛋白受体，属于肿瘤坏死受体 (TNFR) 家族。配体结合后，CD271 可以介导存活或细胞死亡。尽管 CD271 作为肿瘤起始细胞标志物的作用仍有争议，但其在黑色素瘤进展中的作用已得到充分证明。此外，CD271 已被证明在接受化疗和靶向治疗后会上调。在这项研究中，我们证明了通过短的 β-淀粉样蛋白衍生肽 (Aβ(25–35)) 结合化疗或 MAPK 抑制剂激活 CD271 可诱导八种黑色素瘤细胞系的 2D 和 3D 培养细胞凋亡。这种组合治疗显着减少了斑马鱼异种移植模型中的转移，并导致小鼠肿瘤体积显着减少。在来自免疫治疗和靶向治疗耐药患者的离体肿瘤中施用 Aβ(25–35) 可显着减少黑色素瘤细胞的增殖，表明 CD271 的激活可以克服耐药性。Aβ(25–35) 对表达 CD271 的细胞具有特异性，并诱导 CD271 切割和 JNK (pJNK) 的磷酸化。pJNK 与 CD271 的直接蛋白质-蛋白质相互作用导致 PARP1 切割、p53 和 caspase 激活以及 pJNK 依赖性细胞死亡。Aβ(25–35) 还介导线粒体活性氧 (mROS) 积累，从而诱导 CD271 过表达。最后，CD271 上调抑制了 mROS 的产生，揭示了 mROS 调节中存在负反馈回路。这些结果表明靶向 CD271 可以激活细胞死亡途径以抑制黑色素瘤进展并可能克服对靶向治疗的耐药性。意义：特异性激活 CD271 死亡结构域的方法的发现揭示了受体介导的未知途径，并突出了黑色素瘤的新治疗可能性。