Neuzil Jiri, Dong Lan-Feng, Wang Xiu-Fang, Zingg Jean-Marc
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Qld, Australia.
Biochem Biophys Res Commun. 2006 May 19;343(4):1113-7. doi: 10.1016/j.bbrc.2006.03.052. Epub 2006 Mar 31.
Alpha-tocopheryl succinate (alpha-TOS), a redox-silent analogue of vitamin E, induces apoptosis in multiple cell lines in a selective manner, by activating the intrinsic pathway. Since it is a highly hydrophobic compound, it may require a carrier protein for its trafficking to intracellular targets like mitochondria. We studied the role of the ubiquitous tocopherol-associated protein-1 (TAP1 or sec14-like 2) in apoptosis induction by alpha-TOS in malignant mesothelioma (MM) cells. Over-expression of TAP1 in MM cells sensitised them to apoptosis by low doses of alpha-TOS which were sub-apoptotic for the parental cells. Apoptosis induced in TAP1-over-expressing cells was mitochondria- and caspase-dependent, as suggested by dissipation of mitochondrial trans-membrane potential and inhibition by zVAD-fmk, respectively. Binding assays showed affinity of alpha-TOS for TAP1. Finally, TAP1 over-expressing cells accumulated alpha-TOS at higher levels compared to their normal counterparts. We suggest that TAP1 may act as an intracellular shuttle for alpha-TOS, promoting apoptosis initiated by this vitamin E analogue, as shown here for MM cells.
琥珀酸生育酚（α-TOS）是维生素E的一种氧化还原沉默类似物，通过激活内源性途径以选择性方式诱导多种细胞系凋亡。由于它是一种高度疏水的化合物，其转运至线粒体等细胞内靶点可能需要载体蛋白。我们研究了普遍存在的生育酚相关蛋白-1（TAP1或sec14样蛋白2）在α-TOS诱导恶性间皮瘤（MM）细胞凋亡中的作用。MM细胞中TAP1的过表达使它们对低剂量的α-TOS敏感，而这些低剂量对亲代细胞来说是亚凋亡剂量。线粒体跨膜电位的耗散和zVAD-fmk的抑制分别表明，TAP1过表达细胞中诱导的凋亡是线粒体和半胱天冬酶依赖性的。结合试验显示α-TOS对TAP1有亲和力。最后，与正常细胞相比，TAP1过表达细胞积累的α-TOS水平更高。我们认为，TAP1可能作为α-TOS的细胞内转运体，促进这种维生素E类似物引发的凋亡，如本文在MM细胞中所示。
