RESUMEN
Cancer cells reprogram their metabolism to maintain both viability and uncontrolled proliferation. Although an interplay between the genetic, epigenetic and metabolic rewiring in cancer is beginning to emerge, it remains unclear how this metabolic plasticity occurs. Here, we report that in prostate cancer cells (PCCs) microRNAs (miRNAs) greatly contribute to deregulation of mitochondrial fatty acid (FA) oxidation via carnitine system modulation. We provide evidence that the downregulation of hsa-miR-124-3p, hsa-miR-129-5p and hsa-miR-378 induced an increase in both expression and activity of CPT1A, CACT and CrAT in malignant prostate cells. Moreover, the analysis of human prostate cancer and prostate control specimens confirmed the aberrant expression of miR-124-3p, miR-129-5p and miR-378 in primary tumors. Forced expression of the miRNAs mentioned above affected tumorigenic properties, such as proliferation, migration and invasion, in PC3 and LNCaP cells regardless of their hormone sensitivity. CPT1A, CACT and CrAT overexpression allow PCCs to be more prone on FA utilization than normal prostate cells, also in the presence of high pyruvate concentration. Finally, the simultaneous increase of CPT1A, CACT and CrAT is fundamental for PCCs to sustain FA oxidation in the presence of heavy lipid load on prostate cancer mitochondria. Indeed, the downregulation of only one of these proteins reduces PCCs metabolic flexibility with the accumulation of FA-intermediate metabolites in the mitochondria. Together, our data implicate carnitine cycle as a primary regulator of adaptive metabolic reprogramming in PCCs and suggest new potential druggable pathways for prevention and treatment of prostate cancer.
Asunto(s)
Carnitina O-Palmitoiltransferasa/genética , Proteínas de Transporte de Membrana/genética , MicroARNs/genética , Neoplasias de la Próstata/genética , Carcinogénesis/genética , Carnitina/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Ácidos Grasos/genética , Ácidos Grasos/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Oxidación-Reducción , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
Fluoride-releasing restorative dental materials can be beneficial to remineralize dentin and help prevent secondary caries. However, the effects of fluoride release from dental materials on the activity of dental pulp stem cells are not known. Here we investigate whether different fluoride release kinetics from dental resins supplemented with modified hydrotalcite (RK-F10) or fluoride-glass filler (RK-FG10) could influence the behavior of a human dental pulp stem cell subpopulation (STRO-1(+) cells) known for its ability to differentiate toward an odontoblast-like phenotype. The 2 resins, characterized by similar physicochemical properties and fluoride content, exhibited different long-term fluoride release kinetics. Our data demonstrate that long-term exposure of STRO-1(+) cells to a continuous release of a low amount of fluoride by RK-F10 increases their migratory response to transforming growth factor ß1 (TGF-ß1) and stromal cell-derived factor 1 (SDF-1), both important promoters of pulp stem cell recruitment. Moreover, the expression patterns of dentin sialoprotein (dspp), dentin matrix protein 1 (dmp1), osteocalcin (ocn), and matrix extracellular phosphoglycoprotein (mepe) indicate a complete odontoblast-like cell differentiation only when STRO-1(+) cells were cultured on RK-F10. On the contrary, RK-FG10, characterized by an initial fluoride release burst and reduced lifetime of the delivery, did not elicit any significant effect on both STRO-1(+) cell migration and differentiation. Taken together, our results highlight the importance of taking into account fluoride release kinetics in addition to fluoride concentration when designing new fluoride-restorative materials.
Asunto(s)
Cariostáticos/farmacocinética , Materiales Dentales/química , Pulpa Dental/citología , Fluoruros/farmacocinética , Odontogénesis/efectos de los fármacos , Células Madre/efectos de los fármacos , Hidróxido de Aluminio/química , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CXCL12/farmacología , Proteínas de la Matriz Extracelular/metabolismo , Glicoproteínas/metabolismo , Humanos , Cinética , Hidróxido de Magnesio/química , Osteocalcina/metabolismo , Fenotipo , Fosfoproteínas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Saliva Artificial/química , Sialoglicoproteínas/metabolismo , Células Madre/citología , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
A new enzyme showing a dehydrogenase activity towards aromatic aldehydes was isolated, purified and characterized from a halophilic strain isolated from saline environment. The enzyme is a monomer of 54 kDa; it is rather thermostable (optimal temperature: 50 degrees C) showing a broad spectrum of activity in a large pH range with the maximum at pH 9.5. The substrate specificity and the effect of ions were evaluated and compared with analogous described proteins.