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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00025

Molecular, biological and structural features of VL CDR-1 Rb44 peptide, which targets the microtubule network in melanoma cells.

 Natalia Girola1,  Pedro T. Resende-Lara2, Carlos R. Figueiredo1, 3, Mariana H. Massaoka4, Ricardo A. Azevedo1,  Rodrigo L. Cunha5,  Luciano Polonelli6 and  Luiz R. Travassos1, 7*
  • 1Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, Brazil
  • 2Laboratório de Biologia Computacional e Bioinformática, Universidade Federal do ABC, Brazil
  • 3Department of Molecular and Clinical Cancer Medicine, University of Liverpool, United Kingdom
  • 4Cancer Focus, São Paulo, Brazil, Brazil
  • 5Laboratório de Biologia Química, Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Brazil
  • 6Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Italy
  • 7Recepta Biopharma, Brazil

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 VL-CDR1 is a novel peptide that acts on melanoma microtubule network causing cell apoptosis in vitro and melanoma growth inhibition in vivo.

Keywords: Metastatic Melanoma, microtubule, Tubulin (Microtubules), peptide, complementarity-determining region, Apoptosis

Received: 21 Aug 2018; Accepted: 08 Jan 2019.

Edited by:

Jian-ye Zhang, Guangzhou Medical University, China

Reviewed by:

César De La Fuente, Massachusetts Institute of Technology, United States
Chakrabhavi D. Mohan, University of Mysore, India  

Copyright: © 2019 Girola, Resende-Lara, Figueiredo, Massaoka, Azevedo, Cunha, Polonelli and Travassos. 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.

* Correspondence: Prof. Luiz R. Travassos, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil, luiztravassos@gmail.com