INVESTIGADORES
DAVIO Carlos Alberto
artículos
Título:
Multidrug Resistance Protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation.
Autor/es:
COPSEL SABRINA; GARCIA CORINA; DIEZ FEDERICO; VERMEULEN MONICA; BALDI ALBERTO; LILIANA BIANCIOTTI; RUSSEL FG; SHAYO CARINA; DAVIO CARLOS
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Año: 2011 vol. 286 p. 6979 - 6988
ISSN:
0021-9258
Resumen:
Increased intracellular cAMP concentration plays a well
established role in leukemic cell maturation. We previously
reported that U937 cells stimulated by 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 intracellularcAMPlevels not only
in U937 cells but also in other acute myeloid leukemia cell lines
are also regulated by multidrug resistance-associated proteins
(MRPs), particularly MRP4. U937, HL-60, and KG-1a cells,
exposed to amthamine (H2-receptor agonist), augmented intracellularcAMPconcentration
with a concomitant increase in the
efflux. Extrusion ofcAMPwas ATP-dependent and probenecidsensitive,
supporting that the transport was MRP-mediated.
Cells exposed to amthamine and the PDE4 inhibitor showed
enhanced cAMP extrusion, but this response was inhibited by
MRP blockade. Amthamine stimulation, combined with PDE4
and MRP inhibition, induced maximal cell arrest proliferation.
Knockdown strategy by shRNA revealed that this process was
mediated by MRP4. Furthermore, blockade by probenecid or
MRP4 knockdown 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.