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There is increasing evidence that angiotensin II (Ang II), through binding to the type 2 (AT(2)) receptor may have beneficial effects in various physiological and pathological situations. However, specific action presumably mediated by the angiotensin AT(2) receptor has been hampered by the absence of appropriate selective ligands. The aim of this study was to compare the biological properties of two related and selective drug-like nonpeptide AT(2) ligands, namely an agonist called M024 (also known as Compound 21) and a new ligand, presumably an antagonist, C38/M132, (originally called C38). Properties of the compounds were investigated in NG108-15 cells expressing angiotensin AT(2) receptor and known to develop neurite outgrowth upon Ang II stimulation. NG108-15 cells stimulated for three days with C21/M024 (0.1 or 100 nM) exhibited the same neurite outgrowth as cells stimulated with Ang II (100 nM) while co-incubation of Ang II or C21/M024 with C38/M132 (10 or 100 nM) inhibited their effects, similarly to the angiotensin AT(2) receptor antagonist, PD123319 (10 mu M). As Ang II, C21/M024 induced a Rap1-dependent activation of p42/p44(mapk) whereas preincubation of cells with C38/M132 inhibited p42/p44(mapk) and Rap1 activation induced by Ang II. Three-day treatment with C21/M024 or Ang II decreased cell number in culture, an effect that was rescued by preincubation with C38/M132. Taken together, these results indicate that the nonpeptide ligand C21/M024 is a potent angiotensin AT(2) receptor agonist while C38/M132 acts as an antagonist. These selective nonpeptide angiotensin AT(2) ligands may represent unique and long-awaited tools for the pursuit of in vivo studies.

Although Prostate cancer is the most common and second leading cause of cancer-related deaths in American men lack of animal models that faithfully recapitulate histopathological and clinical features of human prostate cancer has hampered prostate cancer research. Taking advantage of a unique androgen-insensitive transgene promoter system we developed a novel genetically-engineered mouse (GEM) model of invasive prostate adenocarcinoma whereby an activating mutation of BRAFV600E has been targeted to the epithelial compartment of the prostate gland. As a first step for the characterization of this model we attempted to assess the requirement for continuous BRAF*-ERK activation in maintenance of established invasive lesions and in progression to androgen-independent state. To our surprise we found that while sufficient to initiate development of AKT-independent invasive prostate adenocarcinoma BRAFV600E is not required for its maintenance. In addition we also demonstrated that BRAF driven ERK and S6K activation alone is not sufficient to drive androgen-independent growth post castration in this mouse model although it appears to be permissive of survival in low androgen state., The original document contains color images.