Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437
Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437
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DOI：
10.1038/sj.onc.1204953
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发表时间：
2001-11-15
期刊：
影响因子：
8
通讯作者：
Kroemer, G
中科院分区：
文献类型：
--
作者：
Belzacq, AS;El Hamel, C;Kroemer, G
越来越多的实验性化疗药物通过直接触发线粒体膜透化（MMP）诱导细胞凋亡。在这里，我们研究了MMP诱导氯尼达明，亚砷酸盐，类维生素A衍生物CD 437。过表达巨细胞病毒编码的蛋白质vMIA（一种与腺嘌呤核苷酸转运蛋白相互作用的蛋白质）的细胞强烈保护免受氯尼达明、亚砷酸盐和CD 437的MMP诱导和致瘤作用。在无细胞系统中，氯尼达明，亚砷酸盐和CD 437诱导ANT脂蛋白体的透化，但对无蛋白脂质体没有影响。ANT依赖的膜透化被两种ANT配体ATP和ADP以及重组Bcl-2蛋白抑制。将氯尼达明、亚砷酸盐和CD 437加入到含有ANT的合成平面脂质双层中，引起ANT通道活性，其电导水平分别为20+/-7，100+/-30和47+/-7 pS。通过抑制糖酵解和/或氧化磷酸化，改变线粒体内膜上建立的ATP/ADP梯度，差异调节氯尼达明、亚砷酸盐和CD 437的杀细胞潜力。无糖酵解抑制的F（0）F（1）ATP酶抑制对氯尼达明诱导的细胞死亡敏感。相反，只有糖酵解和F（0）F（1）ATP酶的联合抑制才能对亚砷酸盐诱导的细胞死亡敏感。通过葡萄糖消耗和/或寡霉素添加，未实现对CD 437诱导的细胞死亡的敏化。这些结果表明ANT是氯尼达明、亚砷酸盐和CD 437的靶点，并揭示了这三种化合物作用模式的意外异质性。
An increasing number of experimental chemotherapeutic agents induce apoptosis by directly triggering mitochondrial membrane permeabilization (MMP). Here we examined MMP induced by lonidamine, arsenite, and the retinoid derivative CD437. Cells overexpressing the cytomegalovirus-encoded protein vMIA, a protein which interacts with the adenine nucleotide translocator, were strongly protected against the MMP-inducing and apoptogenic effects of lonidamine, arsenite, and CD437. In a cell-free system, lonidamine, arsenite, and CD437 induced the permeabilization of ANT proteoliposomes, yet had no effect on protein-free liposomes. The ANT-dependent membrane permeabilization was inhibited by the two ANT ligands ATP and ADP, as well as by recombinant Bcl-2 protein. Lonidamine, arsenite, and CD437, added to synthetic planar lipid bilayers containing ANT, elicited ANT channel activities with clearly distinct conductance levels of 20+/-7, 100+/-30, and 47+/-7 pS, respectively. Altering the ATP/ADP gradient built up on the inner mitochondrial membrane by inhibition of glycolysis and/or oxidative phosphorylation differentially modulated the cytocidal potential of lonidamine, arsenite, and CD437. Inhibition of F(0)F(1)ATPase without glycolysis inhibition sensitized to lonidamine-induced cell death. In contrast, only the combined inhibition of glycolysis plus F(0)F(1)ATPase sensitized to arsenite-induced cell death. No sensitization to cell death induction by CD437 was achieved by glucose depletion and/or oligomycin addition. These results indicate that ANT is a target of lonidamine, arsenite, and CD437 and unravel an unexpected heterogeneity in the mode of action of these three compounds.