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首页> 外文期刊>Biochemistry >Selective Modulation of Protein Kinase C alpha over Protein Kinase C epsilon by Curcumin and Its Derivatives in CHO-K1 Cells
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Selective Modulation of Protein Kinase C alpha over Protein Kinase C epsilon by Curcumin and Its Derivatives in CHO-K1 Cells

机译：姜黄素及其衍生物在CHO-K1细胞中选择性调节蛋白激酶C alpha对蛋白激酶C epsilon的影响

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摘要

Members of the protein kinase C (PKC) family of serine/threonine kinases regulate various cellular functions, including cell growth, differentiation, metabolism, and apoptosis. Modulation of isoform-selective activity of PKC by curcumin (1), the active constituent of Curcuma L., is poorly understood, and the literature data are inconsistent and obscure. The effect of curcumin (1) and its analogues, 4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl] -2-methoxyphenyl oleate (2), (9Z,12Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-l-yl]-2-methoxyphenyl octadeca-9,12-dienoate (3), (9Z,12Z,15Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12,15-trienoate (4), and (1E,6E)-1-[4-(hexadecyloxy)-3-methoxyphenyl]-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (5), and didemethylcurcumin (6) on the membrane translocation of PKC alpha, a conventional PKC, and PKC epsilon, a novel PKC, has been studied in CHO-K1 cells, in which these PKC isoforms are endogenously expressed. Translocation of PKC from the cytosol to the membrane was measured using immunoblotting and confocal microscopy. 1 and 6 inhibited the TPA-induced membrane translocation of PKC alpha but not of PKC epsilon. Modification of the hydroxyl group of curcumin with a long aliphatic chain containing unsaturated double bonds in 2-4 completely abolished this inhibition property. Instead, 2-4 showed significant translocation of PKC alpha but not of PKC epsilon to the membrane. No membrane translocation was observed with 1, 6, or the analogue 5 having a saturated long chain for either PKC alpha or PKC epsilon. 1 and 6 inhibited TPA-induced activation of ERK1/2, and 2-4 activated it. ERK1/2 is the downstream readout of PKC. These results show that the hydroxyl group of curcumin is important for PKC activity and the curcumin template can be useful in developing isoform specific PKC modulators for regulating a particular disease state.
机译：丝氨酸/苏氨酸激酶的蛋白激酶C（PKC）家族成员调节各种细胞功能，包括细胞生长，分化，代谢和凋亡。姜黄素（1）（姜黄的活性成分）对PKC的同工型选择性活性的调节了解甚少，并且文献数据不一致且晦涩难懂。姜黄素（1）及其类似物4-[（（2Z，6E）-3-羟基-7-（4-羟基-3-甲氧基苯基）-5-氧杂庚基-2,6-二烯-1-基]的作用-2-甲氧基苯基油酸酯（2），（9Z，12Z）-4-[（2Z，6E）-3-羟基-7-（4-羟基-3-甲氧基苯基）-5-氧庚基-2,6-dien- 1-基] -2-甲氧基苯基十八烷基-9,12-二烯酸酯（3），（9Z，12Z，15Z）-4-[（2Z，6E）-3-羟基-7-（4-羟基-3-甲氧基苯基） ）-5-氧杂庚-2,6-二烯-1-基] -2-甲氧基苯基十八烷基-9,12,15-三烯酸酯（4）和（1E，6E）-1- [4-（十六烷氧基）-3 -甲氧基苯基] -7-（4-羟基-3-甲氧基苯基）庚-1,6-二烯-3,5-二酮（5）和双二甲基姜黄素（6）对常规PKC的PKCα的膜移位PKC epsilon是一种新型的PKC，已在CHO-K1细胞中进行了研究，其中这些PKC亚型是内源性表达的。使用免疫印迹和共聚焦显微镜测量了PKC从细胞质到膜的转运。图1和图6抑制了TPA诱导的PKCα的膜移位，但不抑制PKCε的膜移位。用含有2-4个不饱和双键的长脂肪族链对姜黄素的羟基进行的修饰完全消除了这种抑制性能。取而代之的是，2-4显示了PKCα明显转移到膜上，而PKC epsilon没有。对于PKCα或PKC epsilon，对于饱和饱和的长链的1、6或类似物5，未观察到膜移位。 1和6抑制TPA诱导的ERK1 / 2激活，而2-4则激活它。 ERK1 / 2是PKC的下游读数。这些结果表明姜黄素的羟基对于PKC活性很重要，并且姜黄素模板可用于开发同工型特异性PKC调节剂以调节特定的疾病状态。

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