Adenosine induces apoptosis in human liver cancer cells through ROS production and mitochondrial dysfunction
Yunfang Ma1, Jun Zhang1, Qi Zhang2
1Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Abstract:
Mitochondria are the most important sensor for apoptosis. Extracellular adenosine is well reported to induce apoptosis of tumor cells. Here we found that extracellular adenosine suppresses the cell growth by induction of apoptosis in BEL-7404 liver cancer cells, and identified a novel mechanism that extracellular adenosine triggers apoptosis by increasing Reactive Oxygen Species (ROS) production and mitochondrial membrane dysfunction in the cells. We observed that adenosine increases ROS production, activates c-Caspase-8 and -9 and Caspase effectors, c-Caspase-3 and c-PARP, induces accumulation of apoptosis regulator Bak, decreases Bcl-xL and Mcl-1, and causes the mitochondrial membrane dysfunction and the release of DIABLO, Cytochrome C, and AIF from mitochondria to cytoplasm in the cells; ROS inhibitor, NAC significantly reduces adenosine-induced ROS production; it also shows the same degree of blocking adenosine-induced loss of mitochondrial membrane potential (MMP) and apoptosis. Our study first observed that adenosine increases ROS production in tumor cells and identified the positive feedback loop for ROS-mediated mitochondrial membrane dysfunction which amplifies the death signals in the cells. Our findings indicated ROS production and mitochondrial dysfunction play a key role in adenosine-induced apoptosis of 7404 cells.
Insights
Extracellular adenosine triggers liver cancer cell death by increasing reactive oxygen species (ROS) and damaging mitochondria. This ROS-mediated mitochondrial dysfunction amplifies apoptosis signals, suppressing tumor growth.
Area of Science:
- Cell Biology
- Biochemistry
- Cancer Research
Background:
- Mitochondria are key regulators of apoptosis.
- Extracellular adenosine is known to induce tumor cell apoptosis.
- The precise mechanisms by which adenosine triggers apoptosis require further elucidation.
Purpose of the Study:
- To investigate the mechanism of extracellular adenosine-induced apoptosis in BEL-7404 liver cancer cells.
- To identify the role of Reactive Oxygen Species (ROS) and mitochondrial dysfunction in this process.
Main Methods:
- Treatment of BEL-7404 cells with extracellular adenosine.
- Measurement of ROS production.
- Analysis of caspase activation and apoptosis regulator protein levels (Bak, Bcl-xL, Mcl-1).
- Assessment of mitochondrial membrane potential (MMP) and release of mitochondrial proteins (DIABLO, Cytochrome C, AIF).
- Use of ROS inhibitor N-acetylcysteine (NAC).
Main Results:
- Extracellular adenosine increased ROS production and induced apoptosis in BEL-7404 cells.
- Adenosine activated caspases (-8, -9, -3) and PARP, altered Bak, Bcl-xL, and Mcl-1 levels, and caused mitochondrial dysfunction.
- Mitochondrial release of DIABLO, Cytochrome C, and AIF was observed.
- NAC significantly reduced adenosine-induced ROS, MMP loss, and apoptosis.
- A positive feedback loop between ROS and mitochondrial dysfunction was identified.
Conclusions:
- Extracellular adenosine induces apoptosis in liver cancer cells via increased ROS production and mitochondrial membrane dysfunction.
- ROS-mediated mitochondrial dysfunction plays a critical role in amplifying adenosine-induced apoptosis signals.
- Targeting ROS production and mitochondrial pathways may offer therapeutic strategies for liver cancer.
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