Induction of cancer cell apoptosis by α-tocopheryl succinate:: molecular pathways and structural requirements
Induction of cancer cell apoptosis by α-tocopheryl succinate:: molecular pathways and structural requirements
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DOI：
10.1096/fj.00-0251com
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发表时间：
2001-02-01
期刊：
影响因子：
4.8
通讯作者：
Weber, C
中科院分区：
文献类型：
--
作者：
Neuzil, J;Weber, T;Weber, C
维生素E类似物α -生育酚琥珀酸酯（α -TOS）可诱导细胞凋亡。我们发现α -TOS在造血和癌细胞系中的促凋亡活性涉及抑制蛋白激酶C (PKC)，因为肉豆蔻酯醋酸磷可以阻止α -TOS引发的细胞凋亡。更多选择性效应表明，α -TOS通过增加蛋白磷酸酶2A （PP2A）活性来降低PKC α同型活性。通过反义寡核苷酸或PKC α过表达证实PKC α抑制在α - tos诱导的细胞凋亡中的作用。bcl-2突变体的功能获得或丧失暗示PKC/PP2A作为α - tos诱导的促凋亡信号的线粒体靶点对bcl-2活性的调节。结构类似物显示α -生育酚和琥珀基都需要最大化这些作用。在结肠癌异种移植小鼠中，α -TOS抑制肿瘤生长80%。这是一种没有已知副作用的药理学相关化合物杀死癌细胞的缩影。
The vitamin E analog alpha -tocopheryl succinate (alpha -TOS) can induce apoptosis. We show that the proapoptotic activity of alpha -TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha -TOS-triggered apoptosis. More selective effecters indicated that alpha -TOS reduced PKC alpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKC alpha inhibition in alpha -TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKC alpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha -TOS-induced proapoptotic signals. Structural analogs revealed that alpha -tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha -TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.