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 microM). Moreover, the presence of excess (100 microM) 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-1beta (1 ng ml-1) and bradykinin (100 nM) was unaffected by these concentrations of tamoxifen. Ionomycin (10 microM) stimulates 3H-AA release by ca. 700% and A23187 (10 microM) by ca. 300% above basal levels. Pre-treatment with tamoxifen (1-20 microM) 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.
Croxtall
J D
JD
Department of Biochemical Pharmacology, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, UK. j.croxtall@qmw.ac.uk
Choudhury
Q
Q
White
J O
JO
Flower
R J
RJ
D017305:Annexin A1 / Q000502:physiology; D016718:Arachidonic Acid / Q000378:metabolism*; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D017305:Annexin A1; D004965:Estrogen Antagonists; D007375:Interleukin-1; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D016718:Arachidonic Acid; D000001:Calcimycin; D015759:Ionomycin; D004815:Epidermal Growth Factor; D019284:Thapsigargin; D010741:Phospholipases A; D001920:Bradykinin