title: Hydrogen peroxide regulates cell adhesion through the redox sensor RPSA.
abstract: To become metastatic, a tumor cell must acquire new adhesion properties that allow migration into the surrounding connective tissue, transmigration across endothelial cells to reach the blood stream and, at the site of metastasis, adhesion to endothelial cells and transmigration to colonize a new tissue. Hydrogen peroxide (H2O2) is a redox signaling molecule produced in tumor cell microenvironment with high relevance for tumor development. However, the molecular mechanisms regulated by H2O2 in tumor cells are still poorly known. The identification of H2O2-target proteins in tumor cells and the understanding of their role in tumor cell adhesion are essential for the development of novel redox-based therapies for cancer. In this paper, we identified Ribosomal Protein SA (RPSA) as a target of H2O2 and showed that RPSA in the oxidized state accumulates in clusters that contain specific adhesion molecules. Furthermore, we showed that RPSA oxidation improves cell adhesion efficiency to laminin in vitro and promotes cell extravasation in vivo. Our results unravel a new mechanism for H2O2-dependent modulation of cell adhesion properties and identify RPSA as the H2O2 sensor in this process. This work indicates that high levels of RPSA expression might confer a selective advantage to tumor cells in an oxidative environment.
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: favilas-boas@fc.ul.pt.
authors.forename: Filipe
authors.initials: F
authors.lastname: Vilas-Boas
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: anabagulho@gmail.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Bagulho
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: rita_tenente@hotmail.com.
authors.forename: Rita
authors.initials: R
authors.lastname: Tenente
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: vhteixeira@fc.ul.pt.
authors.forename: Vitor H
authors.initials: VH
authors.lastname: Teixeira
authors.affiliation: Instituto Gulbenkian de Ciência, R. Quinta Grande 6, 2780-156 Oeiras, Portugal; CE3C - Centre for Ecology, Evolution and Environmental Changes, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal. Electronic address: gaby@igc.gulbenkian.pt.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Martins
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: gmcosta@fc.ul.pt.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: da Costa
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: ajeronimosousa@gmail.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Jerónimo
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: cacordeiro@fc.ul.pt.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordeiro
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: mamachuqueiro@fc.ul.pt.
authors.forename: Miguel
authors.initials: M
authors.lastname: Machuqueiro
authors.affiliation: Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: csafonso@fc.ul.pt.
authors.forename: Carla
authors.initials: C
authors.lastname: Real
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D019012:Integrin beta1 / Q000502:physiology; D007797:Laminin / Q000502:physiology; D010084:Oxidation-Reduction; D017474:Receptors, Laminin / Q000502:physiology*; D012269:Ribosomal Proteins / Q000502:physiology*
chemical_list: D004220:Disulfides; D019012:Integrin beta1; D007797:Laminin; C510624:RPSA protein, human; D017474:Receptors, Laminin; D012269:Ribosomal Proteins; D006861:Hydrogen Peroxide; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: Cell adhesion; Extravasation; Hydrogen peroxide; Integrin signaling; RPSA; Redox signaling