Kinins and their receptors have been recently implicated in cancer.
Using functional and molecular approaches, we investigated the relevance of kinin B(1) and B(2) receptors in bladder cancer. Functional studies were conducted using bladder cancer cell lines, and human biopsies were employed for molecular studies. Both B(1) des-Arg(9)-BK and B(2) BK receptor agonists stimulated the proliferation of grade 3-derived T24 bladder cancer cells. Furthermore, treatment with B(1) and B(2) 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-Arg(9)-BK completely failed to induce its proliferation. Real-time PCR revealed that the mRNA expression of kinin receptors, particularly B(1) receptors, was increased in T24 cells relative to RT4 cells. Data from bladder cancer human biopsies revealed that B(1) 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-Arg(9)-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 B(1) 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.
Written by:
Sgnaolin V, Pereira TC, Bogo MR, Zanin R, Battastini AM, Morrone FB, Campos MM. Are you the author?
Prostgraduate Program in Medicine and Health Sciences, Pontificia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Partenon, 90619-900, Porto Alegre, RS, Brazil.
Reference: Invest New Drugs. 2012 Dec 7 (Epub ahead of print)
PubMed Abstract
PMID: 23224295
