Growth-independent induction of spermidine transport by IL-4 and IL-13 in ZR-75-1 human breast cancer cells

Abstract

Polyamine transport is strongly induced by insulin and estradiol (E2) in ZR-75-1 human breast cancer cells. Because signal transduction mechanisms of insulin and interleukin-4 (IL-4) partly overlap, we have compared the ability of these agents as well as that of interleukin-13 (IL-13), a cytokine that often mimics IL-4, to modulate spermidine transport in these cells. In the presence of E2, insulin increased DNA content and the rate of [3H]spermidine uptake by 2.1- and 3.7-fold, respectively, after an 8-day incubation, whereas the sole addition of IL-4 caused a quantitatively similar induction of [3H]spermidine uptake while leaving cell growth unaffected. No comparable induction of spermidine transport was observed with interleukins-1 alpha and -6, and the effect of IL-4 was not additive to that elicited by insulin plus E2. IL-4 and IL-13 stimulated [3H]spermidine uptake to a comparable extent, with half-maximal effects observed at 80 and 400 pg/ml, respectively. Interferon-gamma inhibited IL-4- and IL-13-dependent spermidine uptake to a much greater extent than basal or insulin-induced transport of the polyamine. IL-4 and IL-13 increased the Vmax and K(m) of [3H]spermidine uptake by about 4- and 2.5-fold, respectively. Na(+)-dependent amino acid uptake was increased by insulin but not by IL-4 or IL-13, indicating that the cytokines do not induce a general increase in membrane transport activity. IL-4 and IL-13 did not interfere with feedback inhibition of polyamine uptake, and only modestly decreased polyamine content after prolonged incubation, suggesting that these cytokines stimulate spermidine uptake by increasing total transport capacity rather than by repressing and endogenous inhibitor.