title: The Ig VHcomplementarity-determining region 3-containing Rb9 peptide, inhibits melanoma cells migration and invasion by interactions with Hsp90 and an adhesion G-protein coupled receptor.
abstract: 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 hypervariable 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-Nex2 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.
authors: Department of Microbiology, Immunology and Parasitology, Cell Biology Division and Experimental Oncology Unit (UNONEX), Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors: Natalia
authors: N
authors: Girola
authors: Interdepartmental Group of Health Economics (Grides), Federal University of São Paulo, SP, Brazil.
authors: Alisson L
authors: AL
authors: Matsuo
authors: Department of Microbiology, Immunology and Parasitology, Cell Biology Division and Experimental Oncology Unit (UNONEX), Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors: Carlos R
authors: CR
authors: Figueiredo
authors: Department of Microbiology, Immunology and Parasitology, Cell Biology Division and Experimental Oncology Unit (UNONEX), Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors: Mariana H
authors: MH
authors: Massaoka
authors: Department of Microbiology, Immunology and Parasitology, Cell Biology Division and Experimental Oncology Unit (UNONEX), Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors: Camyla F
authors: CF
authors: Farias
authors: Núcleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes, São Paulo, SP, Brazil.
authors: Denise C
authors: DC
authors: Arruda
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, São Paulo, SP, Brazil.
authors: Ricardo A
authors: RA
authors: Azevedo
authors: Center for Cellular and Molecular Therapy (CTCMol) and Department of Biochemistry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors: Hugo P
authors: HP
authors: Monteiro
authors: Computation and Bioinformatic Biology laboratory, Federal University of ABC, Santo André, São Paulo, SP, Brazil.
authors: Pedro T
authors: PT
authors: Resende-Lara
authors: Chemical Biology Laboratory, Natural and Human Sciences Center, Federal University of ABC, Santo André, São Paulo, SP, Brazil.
authors: Rodrigo L O R
authors: RL
authors: Cunha
authors: Microbiology and Virology Unit, Department of Biomedical, Biotechnological and Translational Sciences, Universitá degli Studi di Parma, Parma, Italy.
authors: Luciano
authors: L
authors: Polonelli
authors: Department of Microbiology, Immunology and Parasitology, Cell Biology Division and Experimental Oncology Unit (UNONEX), Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Recepta Biopharma, São Paulo, SP, Brazil. Electronic address: luiztravassos@gmail.com.
authors: Luiz R
authors: LR
authors: Travassos
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics; D022801:Complementarity Determining Regions / Q000235:genetics* / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000235:genetics / Q000276:immunology; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D022801:Complementarity Determining Regions; D018841:HSP90 Heat-Shock Proteins; D007135:Immunoglobulin Variable Region; D009479:Neuropeptides; D010455:Peptides; C484602:Rac1 protein, mouse; D043562:Receptors, G-Protein-Coupled; C493558:Slc34a2 protein, mouse; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D020830:rac1 GTP-Binding Protein
keywords: Antibody CDRs; Antitumor peptides; Cell migration; G-protein coupled receptor; Hsp90; Melanoma; Metastasis