Rickard K L, Gibson P R, Young G P, Phillips W A
University of Melbourne Department of Medicine, Royal Melbourne Hospital, University of Melbourne Department of Surgery, Western Hospital, Melbourne, Victoria, Australia.
Carcinogenesis. 1999 Jun;20(6):977-84. doi: 10.1093/carcin/20.6.977.
As the colonic epithelium is physiologically exposed to butyrate and to activators of protein kinase C, we examined the effect of the protein kinase C signalling pathway on butyrate-induced expression of markers of differentiation. Activators and inhibitors of protein kinase C were used in combination with butyrate and effects on the expression of markers of differentiation examined in colon cancer cell lines. When the protein kinase C activator phorbol myristate acetate (100 nM) was added for 24 h prior to the addition of 2 mM butyrate, there was a synergistic increase in alkaline phosphatase activity (154 +/- 11% above that for butyrate alone, P = 0.003) in a concentration- and time-dependent manner. Butyrate-induced expression of carcinoembryonic antigen and interleukin-8, dome formation and cell turnover were also markedly augmented by pre-treatment with phorbol myristate acetate. A similar effect was observed with propionate or acetate (but not other differentiating agents), when phorbol myristate acetate and butyrate were added concurrently, or when other protein kinase C activators were used. Pharmacological inhibition of protein kinase C activity did not alter butyrate-induced alkaline phosphatase activity, but abrogated the augmentation induced by phorbol myristate acetate. We conclude that protein kinase C does not mediate the differentiating effects of butyrate on colon cancer cells, but its activation regulates butyrate-induced cellular differentiation.
由于结肠上皮在生理上会接触到丁酸盐和蛋白激酶C的激活剂，我们研究了蛋白激酶C信号通路对丁酸盐诱导的分化标志物表达的影响。将蛋白激酶C的激活剂和抑制剂与丁酸盐联合使用，并检测其对结肠癌细胞系中分化标志物表达的影响。当在添加2 mM丁酸盐之前24小时加入蛋白激酶C激活剂佛波酯肉豆蔻酸酯（100 nM）时，碱性磷酸酶活性呈浓度和时间依赖性协同增加（比单独使用丁酸盐时高154±11%，P = 0.003）。用佛波酯肉豆蔻酸酯预处理也显著增强了丁酸盐诱导的癌胚抗原和白细胞介素-8的表达、穹顶形成和细胞更新。当同时加入佛波酯肉豆蔻酸酯和丁酸盐，或使用其他蛋白激酶C激活剂时，丙酸盐或乙酸盐（但不是其他分化剂）也观察到类似的效果。蛋白激酶C活性的药理学抑制并未改变丁酸盐诱导的碱性磷酸酶活性，但消除了佛波酯肉豆蔻酸酯诱导的增强作用。我们得出结论，蛋白激酶C并不介导丁酸盐对结肠癌细胞的分化作用，但其激活调节丁酸盐诱导的细胞分化。
