title: Modulation of the human equilibrative nucleoside transporter1 (hENT1) activity by IL-4 and PMA in B cells from chronic lymphocytic leukemia.
abstract: Nucleoside transporters (NTs) are essential for the uptake of therapeutic nucleoside analogs, broadly used in cancer treatment. The mechanisms responsible for NT regulation are largely unknown. IL-4 is a pro-survival signal for chronic lymphocytic leukemia (CLL) cells and has been shown to confer resistance to nucleoside analogs. The aim of this study was to investigate whether IL-4 is able to modulate the expression and function of the human equilibrative NT1 (hENT1) in primary cultures of CLL cells and, consequently, to affect cytotoxicity induced by therapeutic nucleosides analogs. We found that treatment with IL-4 (20 ng/ml for 24 h) increased mRNA hENT1 expression in CLL cells without affecting that of normal B cells. Given that the enhanced mRNA levels of hENT1 in CLL cells did not result in increased transport activity, we examined the possibility that hENT1 induced by IL-4 may require post-translational modifications to become active. We found that the acute stimulation of PKC in IL-4-treated CLL cells by short-term incubation with PMA significantly increased hENT1 transport activity and favoured fludarabine-induced apoptosis. By contrast, and in line with previous reports, IL-4 plus PMA protected CLL cells from a variety of cytotoxic agents. Our findings indicate that the combined treatment with IL-4 and PMA enhances hENT1 activity and specifically sensitizes CLL cells to undergo apoptosis induced by fludarabine.
authors: Laboratorio de Inmunología Oncológica, IIHEMA, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors: Paula
authors: P
authors: Fernández Calotti
authors: Carlos María
authors: CM
authors: Galmarini
authors: Cristian
authors: C
authors: Cañones
authors: Romina
authors: R
authors: Gamberale
authors: Daniel
authors: D
authors: Saénz
authors: Julio Sánchez
authors: JS
authors: Avalos
authors: Mónica
authors: M
authors: Chianelli
authors: Ruth
authors: R
authors: Rosenstein
authors: Mirta
authors: M
authors: Giordano
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology* / Q000502:physiology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D015847:Interleukin-4; D014740:Vidarabine; D013755:Tetradecanoylphorbol Acetate; C024352:fludarabine