title: Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia.
abstract: 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.
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina. Laboratorio de Farmacología de Receptores, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Copsel
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.
authors.forename: Ariana
authors.initials: A
authors.lastname: Bruzzone
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.
authors.forename: Maria
authors.initials: M
authors.lastname: May
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Julien
authors.initials: J
authors.lastname: Beyrath
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.
authors.forename: Victoria
authors.initials: V
authors.lastname: Wargon
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Cany
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.
authors.forename: Carina
authors.initials: C
authors.lastname: Shayo
authors.affiliation: Laboratorio de Farmacología de Receptores, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Davio
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D018450:Disease Progression; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008940:Mitotic Index; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics; D020889:Rolipram / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D000242:Cyclic AMP; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D058988:Phosphodiesterase 4 Inhibitors; D034741:RNA, Small Interfering; D020889:Rolipram; C073492:ABCC4 protein, human