Stimulatory effect of thapsigargin, a non-TPA-type tumor promoter, on arachidonic acid metabolism in the murine keratinocyte line HEL30 and on epidermal cell proliferation in vivo as compared to the effects of phorbol ester TPA.
Stimulatory effect of thapsigargin, a non-TPA-type tumor promoter, on arachidonic acid metabolism in the murine keratinocyte line HEL30 and on epidermal cell proliferation in vivo as compared to the effects of phorbol ester TPA.
复制标题
与佛波酯 TPA 的作用相比，毒胡萝卜素（一种非 TPA 型肿瘤促进剂）对小鼠角质形成细胞系 HEL30 中的花生四烯酸代谢和体内表皮细胞增殖的刺激作用。
作者：
F. Marks;B. Hanke;O. Thastrup;G. Fürstenberger
研究了毒胡萝卜素（Tg）（一种非12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）型皮肤肿瘤促进剂）对HEL 30角质形成细胞中花生四烯酸和前列腺素E2（PGE 2）形成以及体外和体内（小鼠皮肤）表皮DNA合成的影响，并与佛波醇酯TPA进行了比较。在摩尔基础上，Tg在诱导花生四烯酸/PGE 2释放方面比TPA强30倍。两种药剂配合使用时，表现出很强的协同作用。该反应主要取决于细胞外介质中Ca 2+的存在。而TPA诱导的释放是由蛋白激酶C（PKC）介导的，Tg诱导的释放不是。与TPA（1 μ M）（其是HEL 30 DNA合成的刺激剂）相反，Tg（0.1-1 μ M）由于显著的细胞毒性效应而抑制体外DNA标记。TPA没有表现出这样的效果。在体内，这两种药物在诱导表皮DNA合成和增生方面几乎是等效的，TPA的刺激潜力比Tg高约10倍。可以得出结论，在体内的增生和肿瘤促进作用的Tg是由于细胞毒性引起的细胞死亡和再生过度增殖。因此，TG诱导的皮肤肿瘤促进似乎类似于机械皮肤创伤的肿瘤促进，而TPA引起更特异性的反应，即PKC介导的反应。由于尽管存在这些机制差异，但两种药物均诱导角质形成细胞中花生四烯酸/PGE 2的立即释放，因此可以认为这种反应提供了刺激性和肿瘤促进的体外参数。
The effect of thapsigargin (Tg), a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type skin tumor promoter, on arachidonic acid and prostaglandin E2 (PGE2) formation in HEL30 keratinocytes and on epidermal DNA synthesis in vitro and in vivo (mouse skin) was investigated and compared with that of the phorbol ester TPA. On a molar basis Tg was 30-fold more potent in inducing the arachidonic acid/PGE2 release than TPA. Applied together, the two agents showed a strong synergistic action. The response critically depended on the presence of Ca2+ in the extracellular medium. While the TPA-induced release was mediated by protein kinase C (PKC) the Tg-induced release was not. In contrast to TPA (1 microM), which is a stimulator of HEL30 DNA synthesis, Tg (0.1-1 microM) inhibited DNA labeling in vitro due to a pronounced cytotoxic effect. TPA did not exhibit such an effect. In vivo both agents were practically equipotent in inducing epidermal DNA synthesis and hyperplasia with TPA having an approximately 10-fold higher irritating potential than Tg. It is concluded that the hyperplasiogenic and tumor-promoting effect of Tg in vivo is due to cytotoxicity causing cell death and regenerative hyperproliferation. Thus, Tg-induced skin tumor promotion seems to resemble tumor promotion by mechanical skin wounding, whereas TPA evokes a more specific, i.e. PKC-mediated response. Since despite these mechanistic differences both agents induce an immediate release of arachidonic acid/PGE2 in keratinocytes, this response may be considered to provide an in vitro parameter for irritancy and tumor promotion.