All-trans-retinoic acid promotes trafficking of human concentrative nucleoside transporter-3 (hCNT3) to the plasma membrane by a TGF-beta1-mediated mechanism.
Human concentrative nucleoside transporter-3 (hCNT3) is a sodium-coupled nucleoside transporter that exhibits high affinity and broad substrate selectivity, making it the most suitable candidate for mediating the uptake and cytotoxic action of most nucleoside-derived drugs. The drug of this class most commonly used in the treatment of chronic lymphocytic leukemia (CLL) is the pro-apoptotic nucleoside analog fludarabine (Flu), which enters CLL cells primarily through human equilibrative nucleoside transporters (hENTs). Although CLL cells lack hCNT3 activity, they do express this transporter protein, which is located mostly in the cytosol. The aim of our study was to identify agents and mechanisms capable of promoting hCNT3 trafficking to the plasma membrane. Here, we report that all-trans-retinoic acid (ATRA), currently used in the treatment of acute promyelocytic leukemia (APL), increases hCNT3-related activity through a mechanism that involves trafficking of pre-existing hCNT3 proteins to the plasma membrane. This effect is mediated by the autocrine action of transforming growth factor (TGF)-beta1, which is transcriptionally activated by ATRA in a p38-dependent manner. TGF-beta1 acts through activation of ERK1/2 and the small GTPase RhoA to promote plasma membrane trafficking of the hCNT3 protein.
Fernández-Calotti
Paula
P
Departament de Bioquímica i Biologia Molecular, the Institut de Biomedicina de la Universitat de Barcelona, and CIBER EHD, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain. pfernandezcalotti@ub.edu
Pastor-Anglada
Marçal
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019898:Autocrine Communication / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D026901:Membrane Transport Proteins; D053773:Transforming Growth Factor beta1; C065171:cif nucleoside transporter; C066737:RHOA protein, human; D014212:Tretinoin; D048052:Mitogen-Activated Protein Kinase 3; D020742:rhoA GTP-Binding Protein; D014740:Vidarabine; C024352:fludarabine