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6-Shogaol as a Novel Thioredoxin Reductase Inhibitor Induces Oxidative-Stress-Mediated Apoptosis in HeLa Cells
Shoujiao Peng1, Shaopeng Yu1, Junmin Zhang2
1The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Abstract:
Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs. 6-Shogaol (6-S), a primary bioactive compound in ginger, has high anticancer activity. However, its potential mechanism of action has not been thoroughly investigated. In this study, we demonstrated for the first time that 6-S, a novel TrxR inhibitor, promoted oxidative-stress-mediated apoptosis in HeLa cells. The other two constituents of ginger, 6-gingerol (6-G) and 6-dehydrogingerduone (6-DG), have a similar structure to 6-S but fail to kill HeLa cells at low concentrations. 6-Shogaol specifically inhibits purified TrxR1 activity by targeting selenocysteine residues. It also induced apoptosis and was more cytotoxic to HeLa cells than normal cells. The molecular mechanism of 6-S-mediated apoptosis involves TrxR inhibition, followed by an outburst of reactive oxygen species (ROS) production. Furthermore, TrxR knockdown enhanced the cytotoxic sensitivity of 6-S cells, highlighting the physiological significance of targeting TrxR by 6-S. Our findings show that targeting TrxR by 6-S reveals a new mechanism underlying the biological activity of 6-S and provides meaningful insights into its action in cancer therapeutics.
Insights
6-Shogaol from ginger inhibits thioredoxin reductase (TrxR), inducing cancer cell death via oxidative stress. This novel mechanism offers new insights for developing anticancer drugs targeting TrxR.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Thioredoxin reductase (TrxR) inhibition is a key strategy in anticancer drug discovery.
- 6-Shogaol (6-S), a ginger compound, exhibits significant anticancer activity, but its mechanism remains unclear.
- Other ginger compounds like 6-gingerol show limited efficacy against cancer cells.
Purpose of the Study:
- To investigate the anticancer mechanism of 6-shogaol in HeLa cells.
- To identify 6-shogaol as a novel thioredoxin reductase inhibitor.
- To elucidate the role of oxidative stress in 6-shogaol-induced apoptosis.
Main Methods:
- Assessing the inhibitory effect of 6-shogaol on purified TrxR1 activity.
- Measuring reactive oxygen species (ROS) production in HeLa cells treated with 6-shogaol.
- Evaluating the cytotoxicity of 6-shogaol on cancer versus normal cells.
- Performing TrxR knockdown experiments to assess sensitivity to 6-shogaol.
Main Results:
- 6-Shogaol was identified as a specific inhibitor of TrxR1, targeting its selenocysteine residues.
- 6-Shogaol treatment led to increased ROS production and apoptosis in HeLa cells.
- 6-Shogaol demonstrated selective cytotoxicity towards HeLa cells compared to normal cells.
- TrxR knockdown potentiated the cytotoxic effects of 6-shogaol, confirming TrxR as the target.
Conclusions:
- 6-Shogaol exerts its anticancer effects by inhibiting TrxR and inducing oxidative-stress-mediated apoptosis.
- Targeting TrxR with 6-shogaol represents a novel therapeutic strategy for cancer treatment.
- This study provides a deeper understanding of 6-shogaol's biological activity and its potential in cancer therapeutics.
