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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >γ-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis
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γ-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis

机译：γ-生育酚或多种维生素E的形式通过中断鞘脂合成诱导人前列腺癌细胞的细胞死亡

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摘要

γ-Tocopherol (γT), the predominant form of vitamin E in diets, but not α-tocopherol, the major vitamin E form in tissues and supplements, inhibits proliferation of prostate cancer cells (LNCaP and PC-3) and lung cancer cells (A549). In contrast, at similar concentrations, γT has no effect on normal prostate epithelial cells. Combinations of some vitamin E forms, such as γT and δ-tocopherol, exhibit additive or synergistic inhibitory effects. In this study, γT or its combination with δ-tocopherol induced apo-ptosis in androgen-sensitive prostate LNCaP, but not in androgen-resistant PC-3 cells, by the induction of cytochrome c release, activation of caspase 9 and caspase 3, cleavage of poly-ADP-ribose polymerase (PARP), and involvement of caspase-independent pathways. Myriocin and fumonisin B1, specific inhibitors of key enzymes (serine palmitoyltransferase and dihydroceramide syn-thase, respectively) in de novo synthesis of sphingolipids, significantly protected cells from γT-induced DNA fragmentation, cytochrome c release, PARP cleavage, and the formation of active caspase 3. Compared with vehicle-treated controls, γT treatment led to pronounced dihydroceramide and dihydrosphingosine accumulation, which preceded morphological and biochemical manifestations of apoptosis. In contrast, ceramide and shpingosine levels did not increase until day 3, when substantial cell death took place. Our study demonstrates that γT and mixed vitamin E forms induce cell death by interrupting the de novo sphingolipid pathway in a prostate cancer cell line. Thus, certain vitamin E forms may be valuable as anticancer agents.
机译：饮食中维生素E的主要形式γ-生育酚（γT），但组织和补品中的主要维生素E形式α-生育酚却不能抑制前列腺癌细胞（LNCaP和PC-3）和肺癌细胞的增殖（ A549）。相反，在相似的浓度下，γT对正常的前列腺上皮细胞没有影响。某些维生素E形式（例如γT和δ-生育酚）的组合具有累加或协同抑制作用。在这项研究中，γT或其与δ-生育酚的组合通过诱导细胞色素c释放，激活caspase 9和caspase 3诱导了雄激素敏感的前列腺LNCaP中的脱垂，但在抗雄激素的PC-3细胞中却没有。 ADP-核糖聚合酶（PARP）的裂解，并参与caspase依赖性途径。从头合成鞘脂的关键酶（分别为丝氨酸棕榈酰转移酶和二氢神经酰胺合酶）的特异抑制剂Myriocin和fumonisin B1显着保护细胞免受γT诱导的DNA片段化，细胞色素c释放，PARP裂解以及活性成分的形成caspase 3.与媒介物处理的对照组相比，γT处理导致明显的二氢神经酰胺和二氢鞘氨醇积累，这先于凋亡的形态学和生化表现。相反，直到第3天，大量细胞死亡时，神经酰胺和shpingosine的水平才增加。我们的研究表明，γT和混合维生素E的形式通过中断前列腺癌细胞系中的从新鞘脂途径诱导细胞死亡。因此，某些形式的维生素E作为抗癌剂可能很有价值。

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