MRP4 REGULATES cAMP LEVELS AND CONTROLS LEUKEMIA CELL

SABRINA COPSEL; CORINA GARCIA; FEDERICO DIEZ; MONICA VERMEULEN; LILIANA G. BIANCIOTTI; FRANS RUSSEL; CARINA SHAYO; CARLOS A. DAVIO

Los Cocos

Congreso; The First South American spring Symposium in Signal Trasducction and Molecular Medicine. (SISTAM 2010); 2010

SISTAM

Increased intracellular cAMP concentration play a well established role in leukemic cell maturation. We previously reported that U937 cells stimulated by histamine H2 receptor agonists, despite a robust increase in cAMP, fail to mature because of rapid H2 receptor desensitization and phosphodiesterase (PDE) activation. Here we show that intracellular cAMP levels in different human AML cell lines are also regulated by multidrug resistanceassociated proteins (MRPs), particularly MRP4. U937, HL-60 and KG-1a cells, exposed to amthamine (H2 receptor agonist), augmented intracellular cAMP concentration with a concomitant increase in the efflux. Extrusion of cAMP was ATP-dependent and probenecid-sensitive, supporting that the transport was MRP mediated. Amthamine stimulation, combined with PDE4 and MRP inhibition, induced maximal cell arrest proliferation. Knock-down strategy by shRNA revealed that this process was mediated by MRP4. Furthermore blockade by probenecid or MRP4 knock-down showed that increased intracellular cAMP levels induce maturation in U937 cells. These findings confirm the key role of intracellular cAMP levels in leukemic cell maturation and provide the first evidence that MRP4 may represent a new potential target for leukemia differentiation therapy.