Huang X P, Fan X T, Desjeux J F, Castagna M
Laboratoires de l'IRSC, Villejuif, France.
Int J Cancer. 1992 Sep 30;52(3):444-50. doi: 10.1002/ijc.2910520319.
Protein kinase C (PKC) is the target for a number of tumor promoters. The mechanism underlying the promoting effects of bile acids in colorectal cancer is not understood. We report that sodium deoxycholate (DOC) triggered activation of PKC in physiological conditions. The biphasic effects of DOC upon PKC activation were Ca(2+)-stimulated and did not require phosphatidylserine (PtdSer) as phospholipid co-factor. The optimal rate of activation was obtained at 0.4 mM DOC and reached approximately half the maximal rate of activation obtained in the presence of PtdSer. Similarly to PtdSer, DOC supported diacylglycerol- as well as phorbol-ester-mediated PKC activation. The reciprocal effects of PtdSer and DOC upon PKC in either 0.5 mM CaCl2 or 0.5 mM EGTA suggest that DOC interacts with the phospholipid-binding domain to elicit PKC activation. DOC-supported enzyme activation exhibited substrate specificity different from that of PtdSer-supported enzyme activation. All tested primary and secondary bile acids activated PKC to various extents, with DOC being the most potent. We suggest that amphipathic bile acids acting in a PtdSer-like manner provide the hydrophobic environment required for PKC activation. Treatment of 32P-labeled platelets and colonic cells HT29 Cl.19A with DOC enhanced the phosphorylation of endogenous substrates for PKC. Colonic cells responsive at 50 microM DOC, appeared to be 10-fold more sensitive than platelets. We suggest that direct or indirect activation of PKC by bile acids may account for the promoting effects of these non-phorbol-ester-type tumor promoters.
蛋白激酶C（PKC）是多种肿瘤促进剂的作用靶点。胆汁酸在结直肠癌中促进作用的潜在机制尚不清楚。我们报告，在生理条件下，脱氧胆酸钠（DOC）可触发PKC的激活。DOC对PKC激活的双相效应是由Ca(2+)刺激的，且不需要磷脂酰丝氨酸（PtdSer）作为磷脂辅因子。在0.4 mM DOC时可获得最佳激活速率，达到在存在PtdSer时获得的最大激活速率的约一半。与PtdSer类似，DOC支持二酰基甘油以及佛波酯介导的PKC激活。PtdSer和DOC在0.5 mM CaCl2或0.5 mM EGTA中对PKC的相互作用表明，DOC与磷脂结合结构域相互作用以引发PKC激活。DOC支持的酶激活表现出与PtdSer支持的酶激活不同的底物特异性。所有测试的初级和次级胆汁酸均不同程度地激活PKC，其中DOC最为有效。我们认为，以类似PtdSer的方式起作用的两亲性胆汁酸提供了PKC激活所需的疏水环境。用DOC处理32P标记的血小板和结肠细胞HT29 Cl.19A可增强PKC内源性底物的磷酸化。在50 microM DOC时产生反应的结肠细胞似乎比血小板敏感10倍。我们认为，胆汁酸对PKC的直接或间接激活可能解释了这些非佛波酯型肿瘤促进剂的促进作用。
