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

• Published in: Biochimica et biophysica acta 1997-11, Vol.1349 (3), p.275-284
• Main Authors: Croxtall, Jamie D, Choudhury, Qam, White, John O, Flower, Rod J
• Format: Article
• Language: English
• Subjects: Annexin A1 - physiology; Arachidonic Acid - metabolism; Bradykinin - pharmacology; Calcimycin - pharmacology; Calcium ionophore; Cell Division - drug effects; Cell Membrane - enzymology; Cell proliferation; Cytosolic PLA 2; Enzyme Activation; Epidermal Growth Factor - pharmacology; Estrogen Antagonists - pharmacology; Humans; ICI 182780; Interleukin-1 - pharmacology; Ionomycin - pharmacology; Lipocortin 1; Phospholipases A - metabolism; Prostaglandin E 2; Receptors, Estrogen - metabolism; Tamoxifen - pharmacology; Thapsigargin - pharmacology; Transforming Growth Factor beta - pharmacology; Tumor Cells, Cultured
• ISSN: 0005-2760; 0006-3002; 1879-145X
• DOI: 10.1016/S0005-2760(97)00143-4

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.