Specific Activation of the CD271 Intracellular Domain in Combination with Chemotherapy or Targeted Therapy Inhibits Melanoma Progression.

Abstract

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.

• Authors: Annalisa Saltari, Andreas Dzung, Marika Quadri, Natascia Tiso, Nicola Facchinello, Alberto Hernández-Barranco, Susana Garcia-Silva, Laura Nogués, Corinne Isabelle Stoffel, Phil F Cheng, Patrick Turko, Ossia M Eichhoff, Francesca Truzzi, Alessandra Marconi, Carlo Pincelli, Héctor Peinado, Reinhard Dummer, Mitchell P Levesque
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 23 Pg. 6044-6057 (12 01 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34645608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Amyloid beta-Peptides
• NGFR protein, human
• Nerve Tissue Proteins
• Receptors, Nerve Growth Factor

Topics

• Amyloid beta-Peptides (pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis
• Cell Proliferation
• Drug Therapy, Combination
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Molecular Targeted Therapy
• Nerve Tissue Proteins (agonists)
• Receptors, Nerve Growth Factor (agonists)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Zebrafish