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.

中文翻译：

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乳腺癌细胞中Cdk5的丢失通过线粒体通透性过渡孔的失调促进ROS介导的细胞死亡。

在许多人类癌症的发生和发展中起作用的Cdk5位于线粒体中，线粒体是凋亡细胞死亡的关键决定因素。Cdk5在乳腺癌细胞中被上调，但已证明Cdk5的丢失会增加化疗诱导的细胞凋亡。但是，Cdk5丢失促进细胞死亡的分子机制仍不清楚。在这里，我们调查Cdk5丢失激活乳腺癌细胞内在的凋亡途径的可能性。我们证明缺乏Cdk5的乳腺癌细胞表现出增加的线粒体去极化，线粒体ROS水平以及与细胞内Ca ²⁺的增加相关的线粒体碎片化水平和钙调神经磷酸酶活性，以及​​DRP1 S637的去磷酸化作用。这些事件伴随凋亡增加，表明Cdk5丢失促进线粒体介导的凋亡。为了定义这种凋亡途径，我们利用了线粒体功能的各种抑制剂。mPTP抑制可完全阻止细胞凋亡，阻断ROS几乎可完全抑制细胞凋亡，而不受线粒体裂变抑制的影响，这表明由于Cdk5丧失而导致的乳腺癌细胞凋亡是通过一种新颖的mPTP依赖性机制发生的，该机制主要通过ROS的增加而起作用。