Tamoxifen inhibits the release of arachidonic acid stimulated by thapsigargin in estrogen receptor-negative A549 cells.

In pre-labelled A549 cells the tumour promoter thapsigargin (50 nM) stimulates the release of [5,6,8,9,11,12,14,15-3H(N)]-arachidonic acid ([3H]-AA) by ca. 300% above basal levels. A549 cells are estrogen receptor negative (ER−), yet this stimulation by thapsigargin is inhibited in a dose-dependent manner by a 3 h pre-treatment with the anti-estrogen tamoxifen (1–20 μM). Moreover, the presence of excess (100 μM) estradiol does not reverse this effect of tamoxifen. Thapsigargin stimulated [3H]-AA release is not inhibited over the same concentration range by 4 hydroxy-tamoxifen nor by the steroidal anti-estrogen ICI 164384. However, the steroidal anti-estrogen ICI 182780 inhibits thapsigargin stimulated [3H]-AA release in a similar manner to tamoxifen and this effect is also not reversed by the presence of excess estradiol. Stimulation of [3H]-AA release by EGF (10 nM), IL-1β (1 ng ml−1) and bradykinin (100 nM) was unaffected by these concentrations of tamoxifen. Ionomycin (10 μM) stimulates [3H]-AA release by ca. 700% and A23187 (10 μM) by ca. 300% above basal levels. Pre-treatment with tamoxifen (1–20μM) inhibits [3H]-AA release stimulated by both these agents and again the presence of excess estradiol does not reverse this effect. Unlike the effects of glucocorticoids on [3H]-AA release in A549 cells the effects of tamoxifen are not reversed by neutralizing anti-bodies to lipocortin 1. Arachidonic acid release is central to cell proliferation in A549 cells and we propose that this action of tamoxifen could explain the anti-proliferative effect seen in these cells and could have important implications for control of cell proliferation of ER− cells in general.