The Ig V-H complementarity-determining region 3-containing Rb9 peptide, inhibits melanoma cells migration and invasion by interactions with Hsp90 and an adhesion G-protein coupled receptor

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Girola, Natalia ; Matsuo, Alisson L. ; Figueiredo, Carlos R. ; Massaoka, Mariana H. ; Farias, Camyla F. ; Arruda, Denise C. ; Azevedo, Ricardo A. ; Monteiro, Hugo P. ; Resende-Lara, Pedro T. ; Cunha, Rodrigo L. O. R. ; Polonelli, Luciano ; Travassos, Luiz R.

• Tipo de documento: Artigo Científico
• Fonte: Peptides; v. 85, p. 1-15, NOV 2016.
• Citações Web of Science: 3

Resumo

The present work aims at investigating the mechanism of action of the Rb9 peptide, which contains the VHCDR 3 sequence of anti-sodium-dependent phosphate transport protein 2B (NaPi2B) monoclonal antibody RebMab200 and displayed antitumor properties. Short peptides corresponding to the hyper variable complementarity-determining regions (CDRs) of immunoglobulins have been associated with antimicrobial, antiviral, immunomodulatory and antitumor activities regardless of the specificity of the antibody. We have shown that the CDR derived peptide Rb9 induced substrate hyperadherence, inhibition of cell migration and matrix invasion in melanoma and other tumor cell lines. Rb9 also inhibited metastasis of murine melanoma in a syngeneic mouse model. We found that Rb9 binds to and interferes with Hsp90 chaperone activity causing attenuation of FAK-Src signaling and downregulation of active Rac1 in B16F10-Next melanoma cells. The peptide also bound to an adhesion G-protein coupled receptor, triggering a concentration-dependent synthesis of cAMP and activation of PKA and VASP signaling as well as IP-3 dependent Ca2+ release. Hsp90 is highly expressed on the cell surface of melanoma cells, and synthetic agents that target Hsp90 are promising cancer therapeutic drugs. Based on their remarkable antitumor effects, the CDR-H3-derived peptides from RebMab200, and particularly the highly soluble and stable Rb9, are novel candidates to be further studied as potential antitumor drugs, selectively acting on cancer cell motility and invasion. (C) 2016 Elsevier Inc. All rights reserved. (AU)

• Processo FAPESP: 10/51423-0 - Peptídeos bioativos e peptidases: atividades biológicas e imunobiológicas em doenças infecciosas e no câncer
• Beneficiário: Luiz Rodolpho Raja Gabaglia Travassos
• Modalidade de apoio: Auxílio à Pesquisa - Temático