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

• Published in: Investigational new drugs Vol. 31; no. 4; pp. 812 - 822
• Main Authors: Sgnaolin, V., Pereira, T. C. B., Bogo, M. R., Zanin, R., Battastini, A. M. O., Morrone, F. B., Campos, M. M.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.08.2013; Springer
• Subjects: Antineoplastic agents; Biological and medical sciences; Medical sciences; Medicine; Medicine & Public Health; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Oncology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Preclinical Studies; Tumors; Tumors of the urinary system; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; B; and B; receptors; MAP kinases; Kinins; Human biopsies; PI3Kγ; T24 and RT4 bladder cancer cells; Kinin; B1 bradykinin receptor; PI3K; Antagonist; Tumor cell; Human; Urinary system disease; Nucleotide sequence; Enzyme; Transferases; Mitogen-activated protein kinase; Urinary tract disease; Malignant tumor; Bladder cancer; B2 bradykinin receptor; Anatomic pathology; Biopsy; Bladder disease; Cancer
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-012-9907-6

Summary 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.