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Investigational New Drugs

, Volume 31, Issue 4, pp 812–822 | Cite as

Functional and molecular characterization of kinin B1 and B2 receptors in human bladder cancer: implication of the PI3Kγ pathway

  • V. Sgnaolin
  • T. C. B. Pereira
  • M. R. Bogo
  • R. Zanin
  • A. M. O. Battastini
  • F. B. Morrone
  • M. M. Campos
PRECLINICAL STUDIES

Summary

Kinins and their receptors have been recently implicated in cancer. Using functional and molecular approaches, we investigated the relevance of kinin B1 and B2 receptors in bladder cancer. Functional studies were conducted using bladder cancer cell lines, and human biopsies were employed for molecular studies. Both B1 des-Arg9-BK and B2 BK receptor agonists stimulated the proliferation of grade 3-derived T24 bladder cancer cells. Furthermore, treatment with B1 and B2 receptor antagonists (SSR240612 and HOE140) markedly inhibited the proliferation of T24 cells. Only higher concentrations of BK increased the proliferation of the grade 1 bladder cancer cell line RT4, while des-Arg9-BK completely failed to induce its proliferation. Real-time PCR revealed that the mRNA expression of kinin receptors, particularly B1 receptors, was increased in T24 cells relative to RT4 cells. Data from bladder cancer human biopsies revealed that B1 receptor expression was increased in all tumor samples and under conditions of chronic inflammation. We also show novel evidence demonstrating that the pharmacological inhibition of PI3Kγ (phosphatidylinositol 3-kinase) with AS252424, concentration-dependently reduced T24 cell proliferation induced by BK or des-Arg9-BK. Finally, the incubation of T24 cells with kinin agonists led to a marked activation of the PI3K/AKT and ERK 1/2 signaling pathways, whereas p38 MAP kinase remained unaffected. Kinin receptors, especially B1 receptors, appear to be implicated in bladder cancer progression. It is tempting to suggest that selective kinin antagonists might represent potential alternative therapies for bladder cancer.

Keywords

Kinins B1 and B2 receptors T24 and RT4 bladder cancer cells Human biopsies PI3Kγ MAP kinases 

Notes

Acknowledgements

This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) and by the FINEP research grant “Implantação, Modernização e Qualificação de Estrutura de Pesquisa da PUCRS” (PUCRSINFRA) # 01.11.0014-00. The manuscript was revised by American Journal Experts for English editing.

Conflict of Interest

The authors declare no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • V. Sgnaolin
    • 1
  • T. C. B. Pereira
    • 1
  • M. R. Bogo
    • 1
  • R. Zanin
    • 2
  • A. M. O. Battastini
    • 3
  • F. B. Morrone
    • 4
  • M. M. Campos
    • 1
  1. 1.Prostgraduate Program in Medicine and Health SciencesPontificia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  2. 2.Institute of Toxicology and PharmacologyPontificia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  3. 3.Departament of BiochemistryUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  4. 4.Prostgraduate Program in Medicine and Health SciencesPUCRSPorto AlegreBrazil

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