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Previous issue date: 2012-03-19 / This study was designed to characterize, by means of functional and molecular approaches, the relevance of kinin B1 and B2 receptors in bladder cancer. Our data clearly shows that both B1 des-Arg9-BK and B2 BK receptor agonists were able to stimulate the proliferation of the grade 3-derived bladder cancer T24 cells. Furthermore, the incubation of B1 and B2 receptor antagonists, SSR240612 and HOE140, respectively, markedly inhibited the proliferation rate of T24 cells. In contrast, only higher concentrations of BK elicited the proliferation of the grade 1 bladder cancer cell line RT4, while des-Arg9-BK incubation completely failed to induce its proliferation. Interestingly, real time PCR experiments revealed that mRNA expression of B2, and mainly B1 receptors was found superior in T24 cells, in comparison to the low malignity grade RT4 cells. Furthermore, data obtained using bladder cancer human biopsies revealed that B1 receptor expression was visibly increased in all tumoral samples or under chronic inflammation of bladder. Concerning the signaling pathways related to the mitogenic effects of kinins, we bring novel evidence showing that pharmacological inhibition of PI3Kg 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 PI3K/AKT and ERK 1/2 signaling pathways, whereas p38 MAP kinase remained unaffected. Our results indicate that kinin B2, and especially B1 receptors appear to be implicated in bladder cancer progression. It is tempting to suggest that selective kinin antagonists might represent potential therapeutic alternatives for bladder cancer control. / O presente estudo teve por objetivo caracterizar, atrav?s de abordagens funcionais e moleculares, a relev?ncia dos receptores B1 e B2 para as cininas no c?ncer de bexiga. Os dados obtidos mostraram que tanto o agonista dos receptores B1, des- Arg9-BK, quanto do receptor B2, BK, foram capazes de estimular a prolifera??o das c?lulas de c?ncer de bexiga grau 3, denominadas T24. Al?m disso, a incuba??o dos antagonistas dos receptores B1 e B2, SSR240612 e HOE140, respectivamente, inibiram acentuadamente a prolifera??o das c?lulas T24. Por outro lado, apenas maiores concentra??es de BK levaram ? prolifera??o das c?lulas de c?ncer de bexiga grau 1 RT4; enquanto a incuba??o com des-Arg9-BK n?o induziu sua prolifera??o. De maneira similar, os resultados revelaram que a express?o de mRNA dos receptores B2 e, principalmente, dos receptores B1 foi superior em c?lulas T24, em compara??o com as c?lulas RT4, que apresentam baixo grau de malignidade. Al?m disso, os dados obtidos com bi?psias de c?ncer de bexiga humano revelaram que a express?o do receptor B1 foi claramente maior em todas as amostras tumorais ou, em uma bi?psia obtida de um quadro de inflama??o cr?nica de bexiga. Em rela??o ?s vias de sinaliza??o relacionadas com os efeitos mitog?nicos das cininas, os dados obtidos mostram que a inibi??o farmacol?gica da PI3Kg com AS252424 reduziu de maneira concentra??o-dependente a prolifera??o das c?lulas T24, quando est? foi induzida por BK ou des-Arg9-BK. Finalmente, a incuba??o das c?lulas T24 com agonistas dos receptores de cininas produziu uma acentuada ativa??o das vias de sinaliza??o PI3K/AKT e ERK 1/2, enquanto a via p38 MAP quinase permaneceu inalterada. Nossos resultados indicam que os receptores de cininas B2 e, especialmente, os receptores B1 parecem estar associados com a progress?o do c?ncer de bexiga. Dessa forma, ? poss?vel sugerir que antagonistas seletivos de receptores de cininas poderiam representar alternativas terap?uticas interessantes para o controle do c?ncer de bexiga.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/1676 |
| Date | 19 March 2012 |
| Creators | Sgnaolin, Vanessa |
| Contributors | Campos, Maria Martha |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Medicina e Ci?ncias da Sa?de, PUCRS, BR, Faculdade de Medicina |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 7620745074616285884, 500, 600, -8624664729441623247 |
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