Modulation of the human equilibrative nucleoside transporter1 (hENT1) activity by IL-4 and PMA in B cells from chronic lymphocytic leukemia.
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.
Fernández Calotti
Paula
P
Laboratorio de Inmunología Oncológica, IIHEMA, Academia Nacional de Medicina, Buenos Aires, Argentina.
Galmarini
Carlos María
CM
Cañones
Cristian
C
Gamberale
Romina
R
Saénz
Daniel
D
Avalos
Julio Sánchez
JS
Chianelli
Mónica
M
Rosenstein
Ruth
R
Giordano
Mirta
M
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
D000970:Antineoplastic Agents; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D015847:Interleukin-4; D014740:Vidarabine; D013755:Tetradecanoylphorbol Acetate; C024352:fludarabine