Jones T, Courage C, Hubbard A, Gescher A
MRC Toxicology Unit, University of Leicester, UK.
Biochem Pharmacol. 1997 May 15;53(10):1413-8. doi: 10.1016/s0006-2952(96)00863-5.
The microbial product staurosporine is a protein kinase C (PKC) inhibitor with some phorbol ester-agonistic properties. It is known to cause the translocation of the PKC isoenzymes epsilon and delta from the cellular cytosol to the membrane and nucleus. We tested the hypothesis that it also affects the cellular localisation of the novel PKC isoenzyme theta, and that staurosporine analogues, some of which are currently under clinical evaluation as potential anticancer drugs, have a similar effect. Their ability to alter PKC-theta distribution was studied in human-derived A549 lung carcinoma cells. Western blot analysis and confocal microscopy after indirect immunofluorescence staining showed that staurosporine (100 nM), like the phorbol ester 12-O-tetradecanoylphorhol-13-acetate (25 nM) caused the translocation of PKC-theta from the cytosol to the membrane and the nucleus. The bisindolylmaleimide GF 109203X mimicked staurosporine, but had a weaker effect. Ro 31-8220 and UCN-01 decreased cytosolic PKC-theta only at 1 microM. CGP 41251 had no effect on PKC-theta in either experimental design. The results show that some, but not all, staurosporine analogues share the partial phorbol ester-agonistic PKC-translocatory activity of the parent molecule.
微生物产物星形孢菌素是一种具有某些佛波酯激动特性的蛋白激酶C（PKC）抑制剂。已知它会导致PKC同工酶ε和δ从细胞胞质溶胶转运至细胞膜和细胞核。我们检验了以下假设：它也会影响新型PKC同工酶θ的细胞定位，并且星形孢菌素类似物（其中一些目前正在作为潜在抗癌药物进行临床评估）具有类似作用。在人源A549肺癌细胞中研究了它们改变PKC-θ分布的能力。间接免疫荧光染色后的蛋白质印迹分析和共聚焦显微镜检查显示，星形孢菌素（100 nM）与佛波酯12-O-十四酰佛波醇-13-乙酸酯（25 nM）一样，会导致PKC-θ从胞质溶胶转运至细胞膜和细胞核。双吲哚马来酰亚胺GF 109203X模拟了星形孢菌素，但作用较弱。Ro 31-8220和UCN-01仅在1 μM时会降低胞质溶胶中的PKC-θ。在任何一种实验设计中，CGP 41251对PKC-θ均无影响。结果表明，一些（但并非全部）星形孢菌素类似物具有母体分子部分佛波酯激动剂的PKC转运活性。
