Croxtall J D, Flower R J
Department of Biochemical Pharmacology, William Harvey Research Institute, Medical College, St. Bartholomew's Hospital, London, United Kingdom.
Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3571-5. doi: 10.1073/pnas.89.8.3571.
The synthetic glucocorticoid dexamethasone (1 microM to 1 pM) strongly (maximum greater than 80%) inhibits proliferation of the A549 human lung adenocarcinoma line (EC50 greater than 1 nM) and leads to the appearance, or a further increase (approximately 3-fold) in the expression on the cell surface, of the calcium and phospholipid binding protein lipocortin (annexin) 1. Both these effects, which are shared by hydrocortisone (1 microM) but not by progesterone or aldosterone (1 microM), are inhibited by the antiglucocorticoids RU38486 and RU43044 (1 microM). The nonsteroidal antiinflammatory drugs indomethacin (1 microM) and naproxen (10 microM) and human recombinant lipocortin 1 (0.05-5.0 micrograms/ml) also produce growth arrest in this cell line. During proliferation A549 cells spontaneously release prostaglandin E2 [10-20 ng (28-57 pmol) per ml per 5-day period] into the growth medium. In concentrations that cause growth-arrest, dexamethasone, indomethacin, and lipocortin 1 abolish the generation of this eicosanoid by A549 cells. Prostaglandin E2 itself (0.01-1 pM) stimulates cell growth and partially reverses (approximately 50%) the inhibition of growth caused by dexamethasone and indomethacin. Addition of the neutralizing anti-lipocortin 1 monoclonal antibody 1A (5 micrograms/ml), but not the nonneutralizing anti-lipocortin monoclonal antibody 1B, substantially reversed (greater than 80%) the inhibitory activity of dexamethasone on both growth and prostaglandin E2 synthesis. The generation of prostaglandin E2 by A549 cells seems to be an important regulator of cell proliferation in vitro and the dexamethasone-induced suppression of proliferation in this model is attributable to eicosanoid inhibition caused by lipocortin 1.
合成糖皮质激素地塞米松（1微摩尔至1皮摩尔）强烈抑制（最大抑制率超过80%）A549人肺腺癌细胞系的增殖（半数有效浓度大于1纳摩尔），并导致钙和磷脂结合蛋白脂皮质素（膜联蛋白）1在细胞表面的表达出现或进一步增加（约3倍）。氢化可的松（1微摩尔）也有这两种作用，但孕酮或醛固酮（1微摩尔）则没有，抗糖皮质激素RU38486和RU43044（1微摩尔）可抑制这两种作用。非甾体抗炎药吲哚美辛（1微摩尔）和萘普生（10微摩尔）以及人重组脂皮质素1（0.05 - 5.0微克/毫升）也能使该细胞系生长停滞。在增殖过程中，A549细胞会自发地将前列腺素E2[每5天每毫升释放10 - 20纳克（28 - 57皮摩尔）]释放到生长培养基中。在导致生长停滞的浓度下，地塞米松、吲哚美辛和脂皮质素1可消除A549细胞产生这种类二十烷酸的现象。前列腺素E2本身（0.01 - 1皮摩尔）可刺激细胞生长，并部分逆转（约50%）地塞米松和吲哚美辛对生长的抑制作用。加入中和性抗脂皮质素1单克隆抗体1A（5微克/毫升），而非非中和性抗脂皮质素单克隆抗体1B，可显著逆转（超过80%）地塞米松对生长和前列腺素E2合成的抑制活性。A549细胞产生前列腺素E2似乎是体外细胞增殖的重要调节因子，在该模型中，地塞米松诱导的增殖抑制归因于脂皮质素1引起的类二十烷酸抑制。
