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Molecular, Biological and Structural Features of V(L) CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells

Microtubules are important drug targets in tumor cells, owing to their role in supporting and determining the cell shape, organelle movement and cell division. The complementarity-determining regions (CDRs) of immunoglobulins have been reported to be a source of anti-tumor peptide sequences, indepen...

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Autores principales: Girola, Natalia, Resende-Lara, Pedro T., Figueiredo, Carlos R., Massaoka, Mariana H., Azevedo, Ricardo A., Cunha, Rodrigo L. O. R., Polonelli, Luciano, Travassos, Luiz R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355703/
https://www.ncbi.nlm.nih.gov/pubmed/30740361
http://dx.doi.org/10.3389/fonc.2019.00025
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author Girola, Natalia
Resende-Lara, Pedro T.
Figueiredo, Carlos R.
Massaoka, Mariana H.
Azevedo, Ricardo A.
Cunha, Rodrigo L. O. R.
Polonelli, Luciano
Travassos, Luiz R.
author_facet Girola, Natalia
Resende-Lara, Pedro T.
Figueiredo, Carlos R.
Massaoka, Mariana H.
Azevedo, Ricardo A.
Cunha, Rodrigo L. O. R.
Polonelli, Luciano
Travassos, Luiz R.
author_sort Girola, Natalia
collection PubMed
description Microtubules are important drug targets in tumor cells, owing to their role in supporting and determining the cell shape, organelle movement and cell division. The complementarity-determining regions (CDRs) of immunoglobulins have been reported to be a source of anti-tumor peptide sequences, independently of the original antibody specificity for a given antigen. We found that, the anti-Lewis B mAb light-chain CDR1 synthetic peptide Rb44, interacted with microtubules and induced depolymerization, with subsequent degradation of actin filaments, leading to depolarization of mitochondrial membrane-potential, increase of ROS, cell cycle arrest at G2/M, cleavage of caspase-9, caspase-3 and PARP, upregulation of Bax and downregulation of Bcl-2, altogether resulting in intrinsic apoptosis of melanoma cells. The in vitro inhibition of angiogenesis was also an Rb44 effect. Peritumoral injection of Rb44L1 delayed growth of subcutaneously grafted melanoma cells in a syngeneic mouse model. L1-CDRs from immunoglobulins and their interactions with tubulin-dimers were explored to interpret effects on microtubule stability. The opening motion of tubulin monomers allowed for efficient L1-CDR docking, impairment of dimer formation and microtubule dissociation. We conclude that Rb44 V(L)-CDR1 is a novel peptide that acts on melanoma microtubule network causing cell apoptosis in vitro and melanoma growth inhibition in vivo.
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spelling pubmed-63557032019-02-08 Molecular, Biological and Structural Features of V(L) CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells Girola, Natalia Resende-Lara, Pedro T. Figueiredo, Carlos R. Massaoka, Mariana H. Azevedo, Ricardo A. Cunha, Rodrigo L. O. R. Polonelli, Luciano Travassos, Luiz R. Front Oncol Oncology Microtubules are important drug targets in tumor cells, owing to their role in supporting and determining the cell shape, organelle movement and cell division. The complementarity-determining regions (CDRs) of immunoglobulins have been reported to be a source of anti-tumor peptide sequences, independently of the original antibody specificity for a given antigen. We found that, the anti-Lewis B mAb light-chain CDR1 synthetic peptide Rb44, interacted with microtubules and induced depolymerization, with subsequent degradation of actin filaments, leading to depolarization of mitochondrial membrane-potential, increase of ROS, cell cycle arrest at G2/M, cleavage of caspase-9, caspase-3 and PARP, upregulation of Bax and downregulation of Bcl-2, altogether resulting in intrinsic apoptosis of melanoma cells. The in vitro inhibition of angiogenesis was also an Rb44 effect. Peritumoral injection of Rb44L1 delayed growth of subcutaneously grafted melanoma cells in a syngeneic mouse model. L1-CDRs from immunoglobulins and their interactions with tubulin-dimers were explored to interpret effects on microtubule stability. The opening motion of tubulin monomers allowed for efficient L1-CDR docking, impairment of dimer formation and microtubule dissociation. We conclude that Rb44 V(L)-CDR1 is a novel peptide that acts on melanoma microtubule network causing cell apoptosis in vitro and melanoma growth inhibition in vivo. Frontiers Media S.A. 2019-01-25 /pmc/articles/PMC6355703/ /pubmed/30740361 http://dx.doi.org/10.3389/fonc.2019.00025 Text en Copyright © 2019 Girola, Resende-Lara, Figueiredo, Massaoka, Azevedo, Cunha, Polonelli and Travassos. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Girola, Natalia
Resende-Lara, Pedro T.
Figueiredo, Carlos R.
Massaoka, Mariana H.
Azevedo, Ricardo A.
Cunha, Rodrigo L. O. R.
Polonelli, Luciano
Travassos, Luiz R.
Molecular, Biological and Structural Features of V(L) CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells
title Molecular, Biological and Structural Features of V(L) CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells
title_full Molecular, Biological and Structural Features of V(L) CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells
title_fullStr Molecular, Biological and Structural Features of V(L) CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells
title_full_unstemmed Molecular, Biological and Structural Features of V(L) CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells
title_short Molecular, Biological and Structural Features of V(L) CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells
title_sort molecular, biological and structural features of v(l) cdr-1 rb44 peptide, which targets the microtubule network in melanoma cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355703/
https://www.ncbi.nlm.nih.gov/pubmed/30740361
http://dx.doi.org/10.3389/fonc.2019.00025
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