title: Activation of the kinin B1 receptor attenuates melanoma tumor growth and metastasis.
abstract: Melanoma is a very aggressive tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies. Furthermore, acquiring the ability to metastasize in melanoma and many other tumor types is directly related to incurable disease. The B1 kinin receptor participates in a variety of cancer-related pathophysiological events, such as inflammation and angiogenesis. Therefore, we investigated whether this G protein-coupled receptor plays a role in tumor progression. We used a murine melanoma cell line that expresses the kinin B1 receptor and does not express the kinin B2 receptor to investigate the precise contribution of activation of the B1 receptor in tumor progression and correlated events using various in vitro and in vivo approaches. Activation of the kinin B1 receptor in the absence of B2 receptor inhibits cell migration in vitro and decreases tumor formation in vivo. Moreover, tumors formed from cells stimulated with B1-specific agonist showed several features of decreased aggressiveness, such as smaller size and infiltration of inflammatory cells within the tumor area, higher levels of pro-inflammatory cytokines implicated in the host anti-tumor immune response, lower number of cells undergoing mitosis, a poorer vascular network, no signs of invasion of surrounding tissues or metastasis and increased animal survival. Our findings reveal that activation of the kinin B1 receptor has a host protective role during murine melanoma tumor progression, suggesting that the B1 receptor could be a new anti-tumor GPCR and provide new opportunities for therapeutic targeting.
authors.affiliation: Department of Biochemistry and Immunology, Faculty of Medicine at Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dillenburg-Pilla
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Maria
authors.forename: Rosana I
authors.initials: RI
authors.lastname: Reis
authors.forename: Elaine Medeiros
authors.initials: EM
authors.lastname: Floriano
authors.forename: Cacilda Dias
authors.initials: CD
authors.lastname: Pereira
authors.forename: Fernando Luiz
authors.initials: FL
authors.lastname: De Lucca
authors.forename: Simone Gusmão
authors.initials: SG
authors.lastname: Ramos
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Miriam G
authors.initials: MG
authors.lastname: Jasiulionis
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Costa-Neto
mesh_terms: D000704:Analysis of Variance; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D059648:Kisspeptins / Q000378:metabolism; D008545:Melanoma / Q000503:physiopathology / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D043783:Receptor, Bradykinin B1 / Q000819:agonists / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D005456:Fluorescent Dyes; C106628:KISS1 protein, human; D059648:Kisspeptins; D043783:Receptor, Bradykinin B1; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue