Ward N E, O'Brian C A
Department of Cell Biology, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Carcinogenesis. 1988 Aug;9(8):1451-4. doi: 10.1093/carcin/9.8.1451.
Protein kinase C (PKC) is a Ca2+- and phospholipid-dependent protein kinase which binds and is activated by tumor promoters such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). PKC can be activated in vitro by phosphatidylserine (PS) plus either TPA or Ca2+. We report here that the bile acid analog fusidic acid can replace the requirement for PS in the activation of PKC by TPA. In addition, fusidic acid can enhance the activation of PKC by Ca2+ and PS as well as by TPA and PS. Fusidic acid is an excellent model compound for in vitro studies of the direct effects of bile acids on PKC activity because, unlike many bile acids, it is completely soluble in standard PKC assay mixtures, obviating the exposure of the enzyme and lipid micelles to organic solvents. The colonic mucosa is exposed to millimolar concentrations of bile acids, and we find that fusidic acid stimulates PKC activity in the presence of TPA with a Ka of 350 microM. There is substantial evidence that bile acids are endogenous tumor promoters, and that colon carcinogenesis is influenced by the composition of bile acids in vivo. Thus, fusidic acid may be a prototype of bile acids which could mediate tumor promotion, at least in part, by replacing the requirement for PS in the activation of PKC.
蛋白激酶C（PKC）是一种依赖于钙离子和磷脂的蛋白激酶，它能与佛波酯12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）等肿瘤启动子结合并被其激活。PKC在体外可被磷脂酰丝氨酸（PS）加上TPA或钙离子激活。我们在此报告，胆汁酸类似物夫西地酸可以替代PS在TPA激活PKC过程中的需求。此外，夫西地酸可以增强钙离子和PS以及TPA和PS对PKC的激活作用。夫西地酸是用于体外研究胆汁酸对PKC活性直接影响的优秀模型化合物，因为与许多胆汁酸不同，它在标准PKC测定混合物中完全可溶，避免了酶和脂质微团暴露于有机溶剂。结肠黏膜会接触到毫摩尔浓度的胆汁酸，我们发现夫西地酸在TPA存在的情况下能刺激PKC活性，其解离常数（Ka）为350微摩尔。有大量证据表明胆汁酸是内源性肿瘤启动子，且体内胆汁酸的组成会影响结肠癌的发生。因此，夫西地酸可能是胆汁酸的一个原型，它至少可以部分地通过替代PS在PKC激活中的需求来介导肿瘤促进作用。
