Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation.
Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation.
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DOI：
10.1038/cddis.2014.419
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发表时间：
2014-10-23
影响因子：
9
通讯作者：
White C
中科院分区：
文献类型：
--
作者：
Huang H;Shah K;Bradbury NA;Li C;White C
Mcl - 1是Bcl - 2家族的一种抗凋亡成员，在非小细胞肺癌（NSCLC）中经常上调。我们现在报道了在非小细胞肺癌细胞系中Mcl - 1与线粒体外膜定位的电压依赖性阴离子通道（VDAC）之间相互作用的生理学意义。Mcl - 1与VDAC1和3亚型高亲和力结合，但与VDAC2结合非常弱，并且基于VDAC1序列的肽段可破坏这种结合。在A549细胞中，降低Mcl - 1表达水平或应用基于VDAC的肽段限制了Ca²⁺摄入线粒体基质，其结果是抑制了活性氧（ROS）的产生。在A549、H1299和H460细胞中，Mcl - 1敲低和基于VDAC的肽段都减弱了细胞迁移，但不影响细胞增殖。通过实验恢复ROS水平可挽救Mcl - 1敲低细胞的迁移，这与ROS产生驱动迁移增加的模型一致。这些数据表明，Mcl - 1和VDAC之间的相互作用通过一种涉及Ca²⁺依赖性ROS产生的机制促进肺癌细胞迁移。
Mcl-1 is an antiapoptotic member of the Bcl-2 family frequently upregulated in non-small cell lung carcinoma (NSCLC). We now report the physiological significance of an interaction between Mcl-1 and the mitochondrial outer membrane-localized voltage-dependent anion channel (VDAC) in NSCLC cell lines. Mcl-1 bound with high affinity to VDAC1 and 3 isoforms but only very weakly to VDAC2 and binding was disrupted by peptides based on the VDAC1 sequence. In A549 cells, reducing Mcl-1 expression levels or application of VDAC-based peptides limited Ca2+ uptake into the mitochondrial matrix, the consequence of which was to inhibit reactive oxygen species (ROS) generation. In A549, H1299 and H460 cells, both Mcl-1 knockdown and VDAC-based peptides attenuated cell migration without affecting cell proliferation. Migration was rescued in Mcl-1 knockdown cells by experimentally restoring ROS levels, consistent with a model in which ROS production drives increased migration. These data suggest that an interaction between Mcl-1 and VDAC promotes lung cancer cell migration by a mechanism that involves Ca2+-dependent ROS production.
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DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Luanpitpong, Sudjit;Talbott, Siera Jo;Chanvorachote, Pithi
通讯作者：
Chanvorachote, Pithi
影响因子：
7.4
作者：
Kowaltowski, AJ;Fenton, RG;Fiskum, G
通讯作者：
Fiskum, G
影响因子：
56.9
作者：
Ishikawa, Kaori;Takenaga, Keizo;Hayashi, Jun-Ichi
通讯作者：
Hayashi, Jun-Ichi