Bradykinin promotes murine melanoma cell migration and invasion through endogenous production of superoxide and nitric oxide

Roberta Eller-Borges; Elaine G Rodrigues; Ana Caroline S Teodoro; Miriam S Moraes; Denise C Arruda; Thaysa Paschoalin; Marli F Curcio; Paulo E da Costa; Igor R Do Nascimento; Leandro A Calixto; Arnold Stern; Hugo P Monteiro; Wagner L Batista

doi:10.1016/j.niox.2023.01.006

Bradykinin promotes murine melanoma cell migration and invasion through endogenous production of superoxide and nitric oxide

Nitric Oxide. 2023 Mar 1:132:15-26. doi: 10.1016/j.niox.2023.01.006. Epub 2023 Feb 2.

Affiliations

¹ Department of Biochemistry, Center for Cellular and Molecular Therapy (CTCMOL), Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
² Department of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, São Paulo, Brazil.
³ Núcleo Integrado de Biotecnologia (NIB), Universidade de Mogi das Cruzes (UMC), Mogi das Cruzes, São Paulo, Brazil.
⁴ Department of Medicine/Infectious Diseases, Universidade Federal de São Paulo, São Paulo, Brazil.
⁵ Department of Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil.
⁶ New York University Grossman School of Medicine, New York, NY, USA.
⁷ Department of Biochemistry, Center for Cellular and Molecular Therapy (CTCMOL), Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. Electronic address: hugo.monteiro@unifesp.br.
⁸ Department of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil. Electronic address: batista@unifesp.br.

PMID: 36736618
DOI: 10.1016/j.niox.2023.01.006

Abstract

Spatial confinement and temporal regulation of signaling by nitric oxide (NO) and reactive oxygen species (ROS) occurs in cancer cells. Signaling mediated by NO and ROS was investigated in two sub clones of the murine melanoma B16F10-Nex2 cell line, Nex10C and Nex8H treated or not with bradykinin (BK). The sub clone Nex10C, similar to primary site cells, has a low capacity for colonizing the lungs, whereas the sub clone Nex8H, similar to metastatic cells, corresponds to a highly invasive melanoma. BK-treated Nex10C cells exhibited a transient increase in NO and an inhibition in basal O₂^- levels. Inhibition of endogenous NO production by l-NAME resulted in detectable levels of O₂^-. l-NAME promoted Rac1 activation and enhanced Rac1-PI3K association. l-NAME in the absence of BK resulted in Nex10C cell migration and invasion, suggesting that NO is a negative regulator of O₂^- mediated cell migration and cell invasion. BK-treated Nex8H cells sustained endogenous NO production through the activation of NOS3. NO activated Rac1 and promoted Rac1-PI3K association. NO stimulated cell migration and cell invasion through a signaling axis involving Ras, Rac1 and PI3K. In conclusion, a role for O₂^- and NO as positive regulators of Rac1-PI3K signaling associated with cell migration and cell invasion is proposed respectively for Nex10C and Nex8H murine melanoma cells.

Keywords: Bradykinin; Murine melanoma; Nitric oxide; Rac1; Ras; Reactive oxygen species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bradykinin* / metabolism
Bradykinin* / pharmacology
Cell Movement
Melanoma*
Mice
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Reactive Oxygen Species / metabolism
Superoxides

Substances

Bradykinin
Superoxides
Nitric Oxide
Reactive Oxygen Species
NG-Nitroarginine Methyl Ester
Phosphatidylinositol 3-Kinases