beta-Actin-binding Complementarity-determining Region 2 of Variable Heavy Chain from Monoclonal Antibody C7 Induces Apoptosis in Several Human Tumor Cells and Is Protective against Metastatic Melanoma

beta-Actin-binding Complementarity-determining Region 2 of Variable Heavy Chain from Monoclonal Antibody C7 Induces Apoptosis in Several Human Tumor Cells and Is Protective against Metastatic Melanoma

Author Arruda, Denise Costa Autor UNIFESP Google Scholar
Santos, Luana Cheven Perbore dos Autor UNIFESP Google Scholar
Melo, Filipe Menegatti de Autor UNIFESP Google Scholar
Pereira, Felipe Valença Autor UNIFESP Google Scholar
Figueiredo, Carlos Rogerio Autor UNIFESP Google Scholar
Matsuo, Alisson Leonardo Autor UNIFESP Google Scholar
Mortara, Renato Arruda Autor UNIFESP Google Scholar
Juliano, Maria Aparecida Autor UNIFESP Google Scholar
Rodrigues, Elaine Guadalupe Autor UNIFESP Google Scholar
Dobroff, Andrey S. Google Scholar
Polonelli, Luciano Google Scholar
Travassos, Luiz Rodolpho Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Recepta Biopharma
Univ Texas MD Anderson Canc Ctr
Univ Parma
Abstract Complementarity-determining regions (CDRs) from monoclonal antibodies tested as synthetic peptides display anti-infective and antitumor activities, independent of the specificity of the native antibody. Previously, we have shown that the synthetic peptide C7H2, based on the heavy chain CDR 2 from monoclonal antibody C7, a mAb directed to a mannoprotein of Candida albicans, significantly reduced B16F10 melanoma growth and lung colony formation by triggering tumor apoptosis. the mechanism, however, by which C7H2 induced apoptosis in tumor cells remained unknown. Here, we demonstrate that C7H2 interacts with components of the tumor cells cytoskeleton, being rapidly internalized after binding to the tumor cell surface. Mass spectrometry analysis and in vitro validation revealed that beta-actin is the receptor of C7H2 in the tumor cells. C7H2 induces beta-actin polymerization and F-actin stabilization, linked with abundant generation of superoxide anions and apoptosis. Major phenotypes following peptide binding were chromatin condensation, DNA fragmentation, annexin V binding, lamin disruption, caspase 8 and 3 activation, and organelle alterations. Finally, we evaluated the cytotoxic efficacy of C7H2 in a panel of human tumor cell lines. All tumor cell lines studied were equally susceptible to C7H2 in vitro. the C7H2 amide without further derivatization significantly reduced lung metastasis of mice endovenously challenged with B16F10-Nex2 melanoma cells. No significant cytotoxicity was observed toward nontumorigenic cell lines on short incubation in vitro or in naive mice injected with a high dose of the peptide. We believe that C7H2 is a promising peptide to be developed as an anticancer drug.
Language English
Sponsor Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number FAPESP: 06/50634-2
FAPESP: 10/51423-0
Date 2012-04-27
Published in Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 287, n. 18, p. 14912-14922, 2012.
ISSN 0021-9258 (Sherpa/Romeo, impact factor)
Publisher Amer Soc Biochemistry Molecular Biology Inc
Extent 14912-14922
Origin http://dx.doi.org/10.1074/jbc.M111.322362
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000304003200054
URI http://repositorio.unifesp.br/handle/11600/34805

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