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Multicolor Flow Cytometry-based Quantification of Mitochondria and Lysosomes in T Cells
Published on: January 9, 2019
Tubeimoside I-induced lung cancer cell death and the underlying crosstalk between lysosomes and mitochondria
Kun Wang1,2, Yujuan Zhan1,3, Bonan Chen1,3
1Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China.
Abstract:
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.
Insights
Tubeimoside I (Tub) inhibits autophagy and disrupts mitochondrial and lysosomal pathways, promoting apoptosis in lung cancer cells. This dual action enhances its anticancer efficacy, as confirmed in mouse models.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Cancer cells develop chemoresistance by upregulating autophagy to protect mitochondrial function.
- Autophagy plays a critical role in cancer cell survival and resistance to chemotherapy.
Purpose of the Study:
- To investigate the anticancer mechanisms of tubeimoside I (Tub) in lung cancer cells.
- To determine if Tub can overcome chemoresistance by targeting autophagy and mitochondria.
Main Methods:
- Treatment of lung cancer cells with Tub.
- Analysis of mitochondrial function, autophagic flux, and apoptosis markers.
- V-ATPase inhibition and lysosomal acidification assays.
- In vivo studies using xenografted mice models.
Main Results:
- Tub inhibited autophagy and disrupted both mitochondrial and lysosomal pathways.
- Tub induced DRP1-mediated mitochondrial fragmentation and blocked autophagic flux by inhibiting V-ATPase.
- Tub caused reactive oxygen species (ROS) accumulation, lysosomal membrane damage, and cathepsin B leakage.
- Cathepsin B upregulated Bax, leading to mitochondrial outer membrane permeabilization and caspase-dependent apoptosis.
- Tub demonstrated significant anticancer effects in xenografted mice.
Conclusions:
- Tub exerts a dual anticancer effect by disrupting mitochondrial and lysosomal pathways and their interaction.
- Tub promotes mitochondria-associated apoptosis in lung cancer cells through a positive feedback loop.
- Tub shows specific and enhanced killing effects on lung cancer cells, offering a potential therapeutic strategy.
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