Tubeimoside I-induced lung cancer cell death and the underlying crosstalk between lysosomes and mitochondria.
Tubeimoside I-induced lung cancer cell death and the underlying crosstalk between lysosomes and mitochondria.
复制标题
Tubeimoside I 诱导的肺癌细胞死亡以及溶酶体和线粒体之间潜在的串扰。
DOI：
10.1038/s41419-020-02915-x
复制
发表时间：
2020
影响因子：
9
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Wang K;Zhan Y;Chen B;Lu Y;Yin T;Zhou S;Zhang W;Liu X;Du B;Wei X;Xiao J
癌细胞已经产生了化疗耐药性，并通过上调保护线粒体功能的自噬机制提高了它们的存活率。在这里，我们报道了传统的中药抗癌药物管贝苷 I (Tub)，它是一种有效的自噬抑制剂，可以促进肺癌细胞中线粒体相关的细胞凋亡。我们发现 Tub 破坏了线粒体和溶酶体途径。其机制之一是诱导 DRP1 介导的线粒体断裂。另一种机制是通过抑制 V-ATP 酶来损害溶酶体酸化，从而阻断晚期自噬流。这会阻止功能失调的线粒体的去除，并导致活性氧（ROS）的积累。过多的 ROS 积累会导致溶酶体膜损伤并增加溶酶体膜通透性，从而导致组织蛋白酶 B 渗漏。最后，组织蛋白酶 B 上调 Bax 介导的线粒体外膜通透性，进而上调胞质细胞色素 C 介导的 caspase 依赖性细胞凋亡。因此，Tub的杀伤癌细胞作用是通过正反馈回路的形成而增强的。 Tub对肺癌细胞的杀伤作用在异种移植小鼠中得到验证。总之，Tub 发挥双重抗癌作用，涉及线粒体和溶酶体途径及其相互作用的破坏，从而对肺癌细胞具有特异性和增强的杀伤作用。
Cancer cells have developed chemoresistance and have improved their survival through the upregulation of autophagic mechanisms that protect mitochondrial function. Here, we report that the traditional Chinese anticancer agent tubeimoside I (Tub), which is a potent inhibitor of autophagy, can promote mitochondria-associated apoptosis in lung cancer cells. We found that Tub disrupted both mitochondrial and lysosomal pathways. One of its mechanisms was the induction of DRP1-mediated mitochondrial fragmentation. Another mechanism was the blocking of late-stage autophagic flux via impairment of lysosomal acidification through V-ATPase inhibition; this blocks the removal of dysfunctional mitochondria and results in reactive oxygen species (ROS) accumulation. Excessive ROS accumulation causes damage to lysosomal membranes and increases lysosomal membrane permeability, which leads to the leakage of cathepsin B. Finally, cathepsin B upregulates Bax-mediated mitochondrial outer membrane permeability and, subsequently, cytosolic cytochrome C-mediated caspase-dependent apoptosis. Thus, the cancer cell killing effect of Tub is enhanced through the formation of a positive feedback loop. The killing effect of Tub on lung cancer cells was verified in xenografted mice. In summary, Tub exerts a dual anticancer effect that involves the disruption of mitochondrial and lysosomal pathways and their interaction and, thereby, has a specific and enhanced killing effect on lung cancer cells.