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) st imulates the release of [5,6,8,9,11,12,14,15-H-3(N)]-arachidonic acid (H-3-AA) by ca. 300% above basal levels. A549 cells are estrogen recep tor negative (ER-), yet this stimulation by thapsigargin is inhibited in a dose-dependent manner by a 3 h pre-treatment with the anti-estrog en tamoxifen (1-20 mu M). Moreover, the presence of excess (100 mu M) estradiol does not reverse this effect of tamoxifen. Thapsigargin stim ulated H-3-AA release is not inhibited over the same concentration ran ge by 4 hydroxy-tamoxifen nor by the steroidal anti-estrogen ICI 16438 4, However, the steroidal anti-estrogen ICI 182780 inhibits thapsigarg in stimulated H-AA release in a similar manner to tamoxifen and this e ffect is also not reversed by the presence of excess estradiol. Stimul ation of H-3-AA release by EGF (10 nM), IL-1 beta (1 ng ml(-1)) and br adykinin (100 mM) was unaffected by these concentrations of tamoxifen. Ionomycin (10 mu M) stimulates H-3-AA release by ca. 700% and A23187 (10 mu M) by ca, 300% above basal levels. Pre-treatment with tamoxifen (1-20 mu M) inhibits H-3-AA release stimulated by both these agents a nd again the presence of excess estradiol does not reverse this effect . Unlike the effects of glucocorticoids on H-3-AA release in A549 cell s the effects of tamoxifen are not reversed by neutralizing anti-bodie s to lipocortin 1. Arachidonic acid release is central to cell prolife ration in A549 cells and we propose that this action of tamoxifen coul d explain the anti-proliferative effect seen in these cells and could have important implications for control of cell proliferation of ER- c ells in general. (C) 1997 Elsevier Science B.V.