2026-04-29T23:03:49Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/260782025-12-18T12:55:58Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991

00925njm 22002777a 4500 dc Saltari, Annalisa author Dzung, Andreas author Quadri, Marika author Tiso, Natascia author Facchinello, Nicola author Hernández-Barranco, Alberto author Garcia-Silva, Susana author Nogués, Laura author Stoffel, Corinne Isabelle author Cheng, Phil F author Turko, Patrick author Eichhoff, Ossia M author Truzzi, Francesca author Marconi, Alessandra author Pincelli, Carlo author Peinado Selgas, Hector author Dummer, Reinhard author Levesque, Mitchell P author 2021-12-01 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) 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 in tumors from immunotherapy- and targeted therapy-resistant patients significantly reduced proliferation of melanoma cells, showing that activation of CD271 can overcome drug resistance. Aβ 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 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. Cancer Res . 2021 Dec 1;81(23):6044-6057 Cancer Research 34645608 https://hdl.handle.net/20.500.12105/26078 P75 NEUROTROPHIN RECEPTOR CELL DEATH APOPTOSIS MECHANISMS PEPTIDE MARKER CANCER Specific Activation of the CD271 Intracellular Domain in Combination with Chemotherapy or Targeted Therapy Inhibits Melanoma Progression.