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Mechanisms involved in kinin-induced glioma cells proliferation: the role of ERK1/2 and PI3K/Akt pathways

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Abstract

Gliomas are the most common malignant brain tumors in adults. Bradykinin (BK) displays an important role in cancer, although the exact role of kinin receptors in the glioma biology remains unclear. This study investigated the role of kinin B1 and B2 receptors (B1R and B2R) on cell proliferation in human glioblastoma cell lineages. The mRNA expression of B1R and B2R was verified by RT-qPCR, whereas the effects of kinin agonists (des-Arg9-BK and BK) were analyzed by cell counting, MTT assay and annexin-V/PI determination. The PI3K/Akt and ERK1/2 signaling activation was assessed by flow cytometry. Our results demonstrated that both human glioblastoma cell lines U-138MG and U-251MG express functional B1R and B2R. The proliferative effects induced by the incubation of des-Arg9-BK and BK are likely related to the activation of PI3K/Akt and ERK 1/2 pathways. Moreover, the pre-incubation of the selective PI3Kγ blocker AS252424 markedly prevented kinin-induced AKT phosphorylation. Noteworthy, the selective B1R and B2R antagonists SSR240612 and HOE-140 were able to induce cell death of either lineages, with mixed apoptosis/necrosis characteristics. Taken together, the present results show that activation of B1R and B2R might contribute to glioblastoma progression in vitro. Furthermore, PI3K/Akt and ERK 1/2 signaling may be a target for adjuvant treatment of glioblastoma with a possible impact on tumor proliferation.

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Acknowledgments

We are grateful to Dr Ana Maria Battastini, from Federal University of Rio Grande do Sul (Brazil), for donating both tested cell lines.

Conflict of interest

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) # 01.11.0014-00, CNPq, CAPES and FAPERGS. NFN is a PhD student in Cellular and Molecular Biology receiving a grant from CAPES/Edital 63/Toxinologia and PROBOLSAS/PUCRS; TCE is an undergraduate student in Pharmacy supported by PIBITI/CNPq and BPA/PUCRS; RFZ is a post-doc fellow supported by PNPD/CAPES; TBP is a PhD student receiving grants from CAPES/PROEX.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil

    Natália Fontana Nicoletti, Rafael Fernandes Zanin, Mauricio Reis Bogo & Fernanda Bueno Morrone

  2. Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil

    Natália Fontana Nicoletti, Rafael Fernandes Zanin, Mauricio Reis Bogo, Maria Martha Campos & Fernanda Bueno Morrone

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

    Thaís Cristina Erig & Fernanda Bueno Morrone

  4. Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil

    Talita Carneiro Brandão Pereira, Mauricio Reis Bogo, Maria Martha Campos & Fernanda Bueno Morrone

  5. Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil

    Mauricio Reis Bogo

  6. Faculdade de Odontologia, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil

    Maria Martha Campos

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  1. Natália Fontana Nicoletti
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  2. Thaís Cristina Erig
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  3. Rafael Fernandes Zanin
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Correspondence to Fernanda Bueno Morrone.

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Nicoletti, N.F., Erig, T.C., Zanin, R.F. et al. Mechanisms involved in kinin-induced glioma cells proliferation: the role of ERK1/2 and PI3K/Akt pathways. J Neurooncol 120, 235–244 (2014). https://doi.org/10.1007/s11060-014-1549-4

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