毒胡萝卜素（一种非佛波酯型肿瘤启动剂）对大鼠腹腔巨噬细胞花生四烯酸代谢的刺激作用分析。

Analysis of the stimulative effect of thapsigargin, a non-TPA-type tumour promoter, on arachidonic acid metabolism in rat peritoneal macrophages.

Ohuchi K, Sugawara T, Watanabe M, Hirasawa N, Tsurufuji S, Fujiki H, Christensen S B, Sugimura T

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.

Br J Pharmacol. 1988 Jul;94(3):917-23. doi: 10.1111/j.1476-5381.1988.tb11604.x.

Abstract

At concentrations above 10 ng ml-1, the tumour promoter thapsigargin stimulates the release of radioactivity from [3H]-arachidonic acid-labelled macrophages harvested from rat peritoneal cavity. 2. The release of radioactivity from prelabelled macrophages was augmented more than additively when the cells were incubated in the medium containing both thapsigargin (10 ng ml-1) and other tumour promoters (10 ng ml-1), such as 12-O-tetradecanoylphorbol-13-acetate (TPA), teleocidin and aplysiatoxin. 3. Thapsigargin required extracellular Ca2+ for the stimulation of arachidonic acid release, while TPA did not. 4. Cytoplasmic free calcium level was increased by thapsigargin treatment but not by TPA treatment. 5. An inhibitor of protein kinases, H-7 inhibited the effect of TPA dose-dependently, whereas H-7 did not inhibit that of thapsigargin. 6. These results suggest that thapsigargin stimulates arachidonic acid release by a mechanism different from that of TPA, viz by acting as a selective Ca2+ mobilizer, but not by activating protein kinase C as TPA does.

摘要

在浓度高于10纳克/毫升时，肿瘤启动子毒胡萝卜素可刺激从大鼠腹腔收获的[3H] - 花生四烯酸标记的巨噬细胞释放放射性物质。2. 当细胞在含有毒胡萝卜素（10纳克/毫升）和其他肿瘤启动子（10纳克/毫升）的培养基中孵育时，预标记巨噬细胞释放的放射性物质增加的幅度超过了叠加效应，这些其他肿瘤启动子如12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）、远侧霉素和海兔毒素。3. 毒胡萝卜素刺激花生四烯酸释放需要细胞外Ca2+，而TPA则不需要。4. 毒胡萝卜素处理可使细胞质游离钙水平升高，而TPA处理则不会。5. 蛋白激酶抑制剂H - 7剂量依赖性地抑制TPA的作用，而H - 7不抑制毒胡萝卜素的作用。6. 这些结果表明，毒胡萝卜素通过与TPA不同的机制刺激花生四烯酸释放，即作为一种选择性Ca2+动员剂起作用，而不像TPA那样通过激活蛋白激酶C起作用。