Artículo
Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia
Copsel, Sabrina Natalia
; Bruzzone, Ariana
; May, Maria
; Beyrath, Julien; Wargon, Victoria
; Cany, Jeannette; Russel, Frans G. M.; Shayo, Carina Claudia
; Davio, Carlos Alberto
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Fecha de publicación:
10/2014
Editorial:
Impact journals
Revista:
Oncotarget
ISSN:
1949-2553
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
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.
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Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos(ININFA)
Articulos de INST.DE INVEST.FARMACOLOGICAS (I)
Articulos de INST.DE INVEST.FARMACOLOGICAS (I)
Citación
Copsel, Sabrina Natalia; Bruzzone, Ariana; May, Maria; Beyrath, Julien; Wargon, Victoria; et al.; Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia; Impact journals; Oncotarget; 5; 19; 10-2014; 9308-9321
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