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Silencing superoxide dismutases (SOD1&SOD2) potentiates ROS-induced apoptosis in chordoma cells
Didem Seven1, Didem Tecimel1,2, Utku Özbey1,2
1Department of Medical Genetics, School of Medicine, Yeditepe University, İstanbul, 34755, Turkey.
Background:
Chordoma, characterized as a slow growing yet locally invasive and destructive bone tumor mainly emerging in the sacrum and clivus, presents a unique challenge due to its rarity, hampering the development of effective treatment strategies. Comprehensive understanding of tumor biology is crucial to suggest novel treatment modalities. Reactive oxygen species (ROS), a family of chemically reactive and unstable oxygen derivatives, are controlled by an intracellular antioxidant system to maintain homeostasis. Higher doses of ROS levels have been associated with the oxidative stress-induced tumor cell death, highlighting the potential of fine-tuning ROS regulation as a target for cancer therapies. The association of ROS mechanism and chordoma remains to be elucidated. In this study, we investigated the effect of targeting the ROS mechanism in chordoma, focusing on superoxide dismutase 1 and superoxide dismutase 2.
Methods:
Two different chordoma datasets were used to assess oxidative stress-related genes. ROS levels and mitochondrial membrane potential (mtMP) in chordoma cells were measured. The gene expression levels of SOD1 and SOD2 in chordoma patients were also evaluated. SOD2 and SOD1 targeted siRNAs were used to silence gene expression in chordoma cells, and quantitative real-time PCR (qRT-PCR) was used to compare gene expression levels. Apoptotic cell populations were determined using flow cytometry.
Results:
The levels of ROS and mtMP were increased in chordoma cell lines compared to healthy nucleus pulposus cells. The chordoma omics data showed induced levels of SOD2. Chordoma tissues also showed high levels of the SOD2 gene. Silencing SOD2 and combined silencing of SOD2 and SOD1 expression increased ROS levels or mtMP, and both induced apoptosis in chordoma cells. ROS imbalance plays a role in chordoma pathogenesis.
Conclusion:
SOD2 and SOD1 might be key enzymes in chordoma to modulate ROS levels, and inhibiting the SOD2 and SOD1 activity might be a potential therapeutic target for chordoma treatment.
Insights
Targeting superoxide dismutase enzymes (SOD1 and SOD2) in chordoma may offer a new therapeutic strategy. Inhibiting these enzymes can increase reactive oxygen species (ROS) and induce cancer cell death.
Area of Science:
- Oncology
- Biochemistry
Background:
- Chordoma is a rare, slow-growing bone tumor requiring novel treatment strategies.
- Reactive oxygen species (ROS) are implicated in cancer cell death, but their role in chordoma is unclear.
- Superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) are key enzymes in managing ROS.
Purpose of the Study:
- To investigate the role of ROS and the SOD enzymes in chordoma.
- To explore the therapeutic potential of targeting SOD1 and SOD2 in chordoma.
Main Methods:
- Analyzed chordoma datasets for oxidative stress-related genes.
- Measured ROS levels and mitochondrial membrane potential (mtMP) in chordoma cells.
- Silenced SOD1 and SOD2 expression using siRNAs and assessed apoptosis via flow cytometry.
Main Results:
- Chordoma cells exhibited higher ROS and mtMP compared to healthy cells.
- Elevated SOD2 expression was observed in chordoma tissues and omics data.
- Silencing SOD2 (alone or with SOD1) increased ROS/mtMP and induced apoptosis in chordoma cells.
Conclusions:
- SOD1 and SOD2 play a significant role in regulating ROS levels in chordoma.
- Inhibiting SOD1 and SOD2 activity presents a potential therapeutic target for chordoma treatment.
