RESUMEN
Iron is often accumulated in the liver during pathological conditions such as cirrhosis and cancer. Elevated expression of glucose transporters GLUT1 and GLUT3 is associated with reduced overall survival in patients with hepatocellular carcinoma. However, it is not known whether iron can regulate glucose transporters and contribute to tumor proliferation. In the present study, we found that treatment of human liver cell line HepG2 with ferric ammonium citrate (FAC) resulted in a significant upregulation of GLUT3 mRNA and protein in a dose-dependent manner. Similarly, iron accumulation in mice fed with high dietary iron as well as in mice injected intraperitoneally with iron dextran enhanced the GLUT3 expression drastically in the liver. We demonstrated that iron-induced hepatic GLUT3 upregulation is mediated by the LKB1/AMPK/CREB1 pathway, and this activation was reversed when treated with iron chelator deferiprone. In addition, inhibition of GLUT3 using siRNA prevented iron-mediated increase in the expression of cell cycle markers and cellular hyperproliferation. Furthermore, exogenous sodium beta-hydroxybutyrate treatment prevented iron-mediated hepatic GLUT3 activation both in vitro and in vivo. Together, these results underscore the importance of iron, AMPK, CREB1 and GLUT3 pathways in cell proliferation and highlight the therapeutic potential of sodium beta-hydroxybutyrate in hepatocellular carcinoma with high GLUT3 expression.
Asunto(s)
Proliferación Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Transportador de Glucosa de Tipo 3 , Hierro , Hígado , Proliferación Celular/efectos de los fármacos , Animales , Humanos , Transportador de Glucosa de Tipo 3/metabolismo , Transportador de Glucosa de Tipo 3/genética , Células Hep G2 , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hierro/metabolismo , Masculino , Proteínas Quinasas Activadas por AMP/metabolismo , Compuestos de Amonio Cuaternario/farmacología , Compuestos Férricos/farmacología , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Quinasas de la Proteína-Quinasa Activada por el AMP/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genéticaRESUMEN
PURPOSE: We investigated the aqueous humor proteome and associated plasma proteome in patients with infectious or noninfectious uveitis. METHODS: AH and plasma were obtained from 28 patients with infectious uveitis (IU), 29 patients with noninfectious uveitis (NIU) and 35 healthy controls undergoing cataract surgery. The proteins profile was analyzed by SomaScan technology. RESULTS: We found 1844 and 2484 proteins up-regulated and 124 and 161 proteins down-regulated in the AH from IU and NIU groups, respectively. In the plasma, three proteins were up-regulated in NIU patients, and one and five proteins were down-regulated in the IU and NIU patients, respectively. The results of pathway enrichment analysis for both IU and NIU groups were related mostly to inflammatory and regulatory processes. CONCLUSION: SomaScan was able to detect novel AH and plasma protein biomarkers in IU and NIU patients. Also, the unique proteins found in both AH and plasma suggest a protein signature that could distinguish between infectious and noninfectious uveitis.