Sako T, Tauber A I, Jeng A Y, Yuspa S H, Blumberg P M
Molecular Mechanisms of Tumor Promotion Section, National Cancer Institute, Bethesda, Maryland 20892.
Cancer Res. 1988 Aug 15;48(16):4646-50.
Staurosporine, a recently described microbial alkaloid, is uniquely potent as an inhibitor of protein kinase C in vitro, being active at nM concentrations rather than the microM concentrations typical of other inhibitor classes. Like these other inhibitors, however, staurosporine exhibits only limited selectivity among different protein kinases. We report here that, in intact human neutrophils, nM concentrations of staurosporine blocked the action of the phorbol ester tumor promoters. In mouse primary epidermal cells, on the other hand, staurosporine failed to block the effects of phorbol 12,13-dibutyrate on epidermal growth factor binding and on induction of ornithine decarboxylase and epidermal transglutaminase. Unexpectedly, staurosporine induced morphological changes in keratinocytes to a dendritic shape resembling that induced by the phorbol esters. It also induced epidermal transglutaminase and cornified envelope production, markers of the differentiative pathway in the epidermal cells. We conclude that the effectiveness of staurosporine as a protein kinase C inhibitor in intact cells may depend markedly on the cell system. Other actions of staurosporine may predominate, and, in keratinocytes, its activity is suggestive of a tumor promoter rather than of an inhibitor of tumor promotion.
星形孢菌素是一种最近被描述的微生物生物碱，在体外作为蛋白激酶C的抑制剂具有独特的强效性，在纳摩尔浓度下就有活性，而不像其他抑制剂类别通常需要微摩尔浓度。然而，与这些其他抑制剂一样，星形孢菌素在不同蛋白激酶之间仅表现出有限的选择性。我们在此报告，在完整的人中性粒细胞中，纳摩尔浓度的星形孢菌素可阻断佛波酯肿瘤启动子的作用。另一方面，在小鼠原代表皮细胞中，星形孢菌素未能阻断佛波醇12,13 - 二丁酸酯对表皮生长因子结合以及对鸟氨酸脱羧酶和表皮转谷氨酰胺酶诱导的影响。出乎意料的是，星形孢菌素诱导角质形成细胞发生形态变化，使其呈树突状，类似于佛波酯所诱导的形状。它还诱导表皮转谷氨酰胺酶和角质化包膜的产生，这些是表皮细胞分化途径的标志物。我们得出结论，星形孢菌素在完整细胞中作为蛋白激酶C抑制剂的有效性可能明显取决于细胞系统。星形孢菌素的其他作用可能占主导地位，并且在角质形成细胞中，其活性表明它是一种肿瘤启动子而非肿瘤促进的抑制剂。
