Nutritional and metabolic signalling through GPCRs.

Deregulated metabolism is a well-known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone-like molecules by activating cell surface G-protein-coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis-derived and ß-oxidation-derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite-sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.

22 : 6n-3 DHA inhibits differentiation of prostate fibroblasts into myofibroblasts and tumorigenesis.

Prostate cancer is one of the most common malignancies in men. Epidemiological and experimental studies have revealed that stromal cells of the tumour microenvironment contribute to the development of prostate cancers, while long-chain n-3 PUFA-enriched diets reduce the risk of this tumour histotype. These findings prompted us to investigate whether DHA, an n-3 PUFA, may abrogate differentiation of prostate fibroblasts into myofibroblasts, the activated form of fibroblasts generally involved in prostate cancer progression. We used the human prostate carcinoma cell line (PC3) as a prostate adenocarcinoma model and found that DHA (1) inhibits α-smooth muscle actin (α-SMA) expression, a typical marker of myofibroblast differentiation, in prostate fibroblasts stimulated in vitro with transforming growth factor-ß (TGF-ß), (2) blocks the matrix metalloproteinase-2-dependent enhanced invasiveness of PC3 prostate adenocarcinoma cells migrated in a medium conditioned by TGF-ß-stimulated prostate fibroblasts, (3) prevents epithelial-mesenchymal transition (EMT) and invasiveness of PC3 cells promoted by a medium conditioned by TGF-ß-stimulated prostate fibroblasts, and (4) reduces the growth rate of tumours obtained in immunodeficient animals injected with PC3 cells plus TGF-ß-stimulated prostate fibroblasts. Moreover, DHA was found to revert α-SMA expression and the invasiveness-promoting activity exerted in PC3 cells by tumoral-activated fibroblasts. Thus, DHA represents a suitable agent to inhibit prostate myofibroblast differentiation, invasiveness and EMT, two most important tumour-promoting activities involved in the progression of prostate cancer cells.