Loss of Cdk5 in breast cancer cells promotes ROS-mediated cell death through dysregulation of the mitochondrial permeability transition pore.
Loss of Cdk5 in breast cancer cells promotes ROS-mediated cell death through dysregulation of the mitochondrial permeability transition pore.
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DOI：
10.1038/s41388-017-0103-1
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发表时间：
2018-03
期刊：
影响因子：
8
通讯作者：
Lee KY
中科院分区：
文献类型：
--
作者：
NavaneethaKrishnan S;Rosales JL;Lee KY
Cdk 5在许多人类癌症的发生和进展中发挥作用，位于线粒体中，线粒体是细胞凋亡的关键决定因素。Cdk5在乳腺癌细胞中上调，但已显示Cdk5损失增加化疗诱导的细胞凋亡。然而，Cdk5缺失促进细胞死亡的分子机制仍不清楚。在这里，我们调查的可能性，Cdk5的损失激活内在的凋亡途径在乳腺癌细胞。我们证明，Cdk5缺陷的乳腺癌细胞表现出增加的线粒体去极化，线粒体ROS水平，和线粒体碎片，这是与细胞内Ca2+水平和钙调磷酸酶活性的增加，和DRP1 S637去磷酸化。这些事件伴随着细胞凋亡的增加，表明Cdk5的损失促进了细胞凋亡介导的细胞凋亡。为了定义这种凋亡途径，我们利用了各种线粒体功能抑制剂。细胞凋亡完全阻止mPTP抑制，几乎完全抑制阻断ROS和线粒体分裂的抑制，表明乳腺癌细胞中的细胞凋亡由于Cdk5损失发生通过一种新的mPTP依赖性机制，主要通过ROS的增加。
Cdk5, which plays a role in the development and progression of many human cancers, localizes in the mitochondria, a key determinant of apoptotic cell death. Cdk5 is upregulated in breast cancer cells but it was shown that Cdk5 loss increases chemotherapy-induced apoptosis. However, the molecular mechanism by which Cdk5 loss promotes cell death remains unclear. Here, we investigate the possibility that Cdk5 loss activates the intrinsic apoptotic pathway in breast cancer cells. We demonstrate that Cdk5-deficient breast cancer cells exhibit increased mitochondrial depolarization, mitochondrial ROS levels, and mitochondrial fragmentation that is associated with an increase in both intracellular Ca2+ level and calcineurin activity, and DRP1 S637 dephosphorylation. These events accompany increased apoptosis, indicating that Cdk5 loss promotes mitochondria-mediated apoptosis. To define this apoptotic pathway, we utilized various inhibitors of mitochondrial function. Apoptosis is completely prevented by mPTP inhibition, almost fully inhibited by blocking ROS and unaffected by inhibition of mitochondrial fission, suggesting that apoptosis in breast cancer cells due to Cdk5 loss occurs via a novel mPTP-dependent mechanism that acts primarily through ROS increase.
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