IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia
Autor/es:
COSPEL, SABRINA; BRUZZONE, ARIANA; MAY, MARIA; BEIRATH, JULIEN; WARGON, V; CANY, JEANNETE; RUSSEL, F; SHAYO, KARINA; DAVIO, CARLOS
Revista:
oncotarget
Editorial:
New York
Referencias:
Año: 2014
ISSN:
1949-2553
Resumen:
Less than a third of adults patients with acute myeloid leukemia (AML) are
cured by current treatments, emphasizing the need for new approaches to therapy.
We previously demonstrated that besides playing a role in drug-resistant leukemia
cell lines, multidrug resistance protein 4 (MRP4/ABCC4) regulates leukemia cell
proliferation and differentiation through the endogenous MRP4/ABCC4 substrate,
cAMP. Here, we studied the role of MRP4/ABCC4 in tumor progression in a mouse
xenograft model and in leukemic stem cells (LSCs) differentiation. We found a
decrease in the mitotic index and an increase in the apoptotic index associated with
the inhibition of tumor growth when mice were treated with rolipram (PDE4 inhibitor)
and/or probenecid (MRPs inhibitor). Genetic silencing and pharmacologic inhibition
of MRP4 reduced tumor growth. Furthermore, MRP4 knockdown induced cell cycle
arrest and apoptosis in vivo. Interestingly, when LSC population was isolated, we
observed that increased cAMP levels and MRP4/ABCC4 blockade resulted in LSCs
differentiation. Taken together, our findings show that MRP4/ABCC4 has a relevant
role in tumor growth and apoptosis and in the eradication of LSCs, providing the basis
for a novel promising target in AML therapy.