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Primary Role for Kinin B1 and B2 Receptors in Glioma Proliferation

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Abstract

This study investigated the role of kinins and their receptors in malignant brain tumors. As a first approach, GL-261 glioma cells were injected (2 × 105 cells in 2 μl/2 min) into the right striatum of adult C57/BL6 wild-type, kinin B1 and B2 receptor knockout (KOB1R and KOB2R) and B1 and B2 receptor double knockout mice (KOB1B2R). The animals received the selective B1R (SSR240612) and/or B2R (HOE-140) antagonists by intracerebroventricular (i.c.v.) route at 5, 10, and 15 days. The tumor size quantification, mitotic index, western blot analysis, quantitative autoradiography, immunofluorescence, and confocal microscopy were carried out in brain tumor samples, 20 days after tumor induction. Our results revealed an uncontrolled tumor growing in KOB1R or SSR240612-treated mice, which was blunted by B2R blockade with HOE-140, suggesting a crosstalk between B1R and B2R in tumor growing. Combined treatment with B1R and B2R antagonists normalized the upregulation of tumor B1R and decreased the tumor size and the mitotic index, as was seen in double KOB1B2R. The B1R was detected on astrocytes in the tumor, indicating a close relationship between this receptor and astroglial cells. Noteworthy, an immunohistochemistry analysis of tumor samples from 16 patients with glioma diagnosis revealed a marked B1R immunopositivity in low-grade gliomas or in older glioblastoma individuals. Furthermore, the clinical data revealed a significantly higher immunopositivity for B1R, when compared to a lower B2R immunolabeling. Taken together, our results show that blocking simultaneously both kinin receptors or alternatively stimulating B1R may be of therapeutic value in the treatment of brain glioblastoma growth and malignancy.

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Acknowledgements

The authors thank Mr. Youssef Haddad for his excellent technical assistance in western blot analysis and Mrs. Julie Verner for her technical support in cell culture at the Université de Montréal. We recognize the expert technical assistance of Mrs. Janaína Silva in the immunohistochemistry analysis. We are grateful to Dr. Marcelo Paglioli Ferreira, Dr. Paulo Valdeci Worm, and Dr. Jorge Luiz Kraemer, from the Department of Neurosurgery, São José Hospital—ISCMPA (Brazil), for donating the human tissue specimens.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Avenida Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil

    Natália Fontana Nicoletti, Maria Martha Campos & Fernanda Bueno Morrone

  2. Instituto de Toxicologia e Farmacologia, PUCRS, Avenida Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil

    Natália Fontana Nicoletti, Maria Martha Campos & Fernanda Bueno Morrone

  3. Department of Molecular and Integrative Physiology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montreal H3C 3J7, QC, Canada

    Jacques Sénécal & Réjean Couture

  4. Laboratório de Patologia, PUCRS, Hospital São Lucas, Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil

    Vinicius Duval da Silva

  5. Serviço de Neurocirurgia, Hospital São José, Irmandade da Santa Casa de Misericórdia de Porto Alegre, Rua Professor Annes Dias 295, Porto Alegre, RS, 90020-090, Brazil

    Marcelo R. Roxo & Nelson Pires Ferreira

  6. Departamento de Biofísica, Universidade Federal de São Paulo, Avenida Doutor Arnaldo 455, Sao Paulo, SP, 01246-903, Brazil

    Rafael Leite T. de Morais & João Bosco Pesquero

  7. Faculdade de Odontologia, Laboratório de Patologia, PUCRS, Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil

    Maria Martha Campos

  8. Laboratório de Farmacologia Aplicada, Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil

    Fernanda Bueno Morrone

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  1. Natália Fontana Nicoletti
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  2. Jacques Sénécal
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Correspondence to Réjean Couture or Fernanda Bueno Morrone.

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All the experimental procedures were in accord to the Principles of Laboratory Animal Care from NIH and approved by the Animal Ethical Committee of the Pontifícia Universidade Católica do Rio Grande do Sul, Brazil (protocol number 11/00258) and Université de Montréal, Canada (protocol number 13-040).

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The authors declare that they have no conflict of interest.

Financial Support

This study was supported by the FINEP research grant “Implantação, Modernização e Qualificação de Estrutura de Pesquisa da PUCRS” (PUCRSINFRA) no. 01.11.0014-00, CNPq, CAPES, and FAPERGS and by the Canadian Institutes of Health Research to RC (MOP-119329).

NFN was a PhD student in Cellular and Molecular Biology receiving a grant from CAPES (AUX-PE/Toxinologia), CAPES/PDSE, and PROBOLSAS/PUCRS.

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Nicoletti, N.F., Sénécal, J., da Silva, V.D. et al. Primary Role for Kinin B1 and B2 Receptors in Glioma Proliferation. Mol Neurobiol 54, 7869–7882 (2017). https://doi.org/10.1007/s12035-016-0265-9

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