Croxtall J D, Choudhury Q, White J O, Flower R J
Department of Biochemical Pharmacology, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, UK.
Biochim Biophys Acta. 1997 Nov 30;1349(3):275-84. 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 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.
在预先标记的A549细胞中，肿瘤启动子毒胡萝卜素（50 nM）可使[5,6,8,9,11,12,14,15-3H(N)]-花生四烯酸（3H-AA）的释放量比基础水平高出约300%。A549细胞为雌激素受体阴性（ER-），然而，用抗雌激素他莫昔芬（1-20 microM）进行3小时预处理后，毒胡萝卜素的这种刺激作用会以剂量依赖的方式受到抑制。此外，过量（100 microM）的雌二醇并不能逆转他莫昔芬的这种作用。在相同浓度范围内，4-羟基他莫昔芬和甾体类抗雌激素ICI 164384均不会抑制毒胡萝卜素刺激的3H-AA释放。然而，甾体类抗雌激素ICI 182780与他莫昔芬类似，也能抑制毒胡萝卜素刺激的3H-AA释放，且过量雌二醇的存在也不能逆转这种作用。表皮生长因子（10 nM）、白细胞介素-1β（1 ng/ml-1）和缓激肽（100 nM）对3H-AA释放的刺激作用不受这些浓度的他莫昔芬影响。离子霉素（10 microM）可使3H-AA的释放量比基础水平高出约700%，A23187（10 microM）则可使其高出约300%。用他莫昔芬（1-20 microM）预处理可抑制这两种物质刺激的3H-AA释放，同样，过量雌二醇的存在也不能逆转这种作用。与糖皮质激素对A549细胞中3H-AA释放的影响不同，他莫昔芬的作用不会被抗脂质皮质素1的中和抗体逆转。花生四烯酸的释放是A549细胞增殖的核心环节，我们认为他莫昔芬的这一作用可以解释在这些细胞中观察到的抗增殖效应，并且可能对一般情况下ER-细胞的增殖控制具有重要意义。
