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Selenium Induces Ferroptosis in Colorectal Cancer Cells via Direct Interaction with Nrf2 and Gpx4
Mengxue Zhao1, Mengyao Xu1, Wei Zhang1
1Department of Pharmacy, Affiliated Huishan Hospital of Xinglin College, Nantong University, Wuxi Huishan District People's Hospital, Wuxi, 214187, Jiangsu Province, China.
Abstract:
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating novel therapeutic strategies. This study demonstrates that high-dose sodium selenite (Na₂SeO₃) induces ferroptosis in CRC cells by directly targeting the Nrf2/Gpx4 antioxidant pathway. Critically, molecular docking analysis confirmed strong binding interactions between Na₂SeO₃ and both the Nrf2 and Gpx4 proteins, suggesting a direct mechanistic link. Clinical samples from CRC patients revealed significantly decreased serum selenium levels, which correlated negatively with tumor markers (CEA, CA199, CA125) and positively with nutritional indicators (hemoglobin, albumin). Immunohistochemistry confirmed elevated Gpx4 and Nrf2 expression in tumor tissues. In vitro experiments using HCT116 cells showed that Na₂SeO₃ treatment inhibited proliferation, increased intracellular Fe2⁺, MDA, and ROS levels, and reduced mitochondrial membrane potential. Western blotting further revealed the downregulation of Nrf2 and Gpx4 proteins upon selenium treatment. Our research findings indicate that sodium selenite may induce ferroptosis by regulating the Nrf2/Gpx4 axis, highlighting its potential as a dual nutrient and pharmacological drug for the treatment of CRC.
Insights
High-dose sodium selenite triggers ferroptosis in colorectal cancer (CRC) cells by inhibiting the Nrf2/Gpx4 antioxidant pathway. Lower selenium levels in CRC patients suggest its therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Nutritional Science
Background:
- Colorectal cancer (CRC) is a major global health concern with high mortality.
- Novel therapeutic strategies are urgently needed for effective CRC treatment.
- The role of selenium in cancer prevention and therapy is under investigation.
Purpose of the Study:
- To investigate the mechanism by which high-dose sodium selenite (Na₂SeO₃) affects colorectal cancer cells.
- To explore the potential of Na₂SeO₃ as a therapeutic agent for CRC by targeting the ferroptosis pathway.
- To correlate serum selenium levels with clinical markers in CRC patients.
Main Methods:
- Molecular docking simulations to assess Na₂SeO₃ binding with Nrf2 and Gpx4.
- Analysis of clinical CRC patient samples for serum selenium levels and tumor markers.
- In vitro studies using HCT116 cells to evaluate Na₂SeO₃ effects on proliferation, oxidative stress (Fe²⁺, MDA, ROS), and mitochondrial function.
- Western blotting to determine Nrf2 and Gpx4 protein expression levels.
Main Results:
- High-dose Na₂SeO₃ was found to induce ferroptosis in CRC cells.
- Molecular docking confirmed direct interactions between Na₂SeO₃ and Nrf2/Gpx4 proteins.
- CRC patients exhibited lower serum selenium levels, negatively correlating with tumor markers and positively with nutritional indicators.
- Na₂SeO₃ treatment in vitro inhibited cell proliferation, increased oxidative stress markers, reduced mitochondrial potential, and downregulated Nrf2 and Gpx4.
- Immunohistochemistry revealed elevated Nrf2 and Gpx4 expression in tumor tissues.
Conclusions:
- Sodium selenite induces ferroptosis in colorectal cancer cells, likely by directly targeting and downregulating the Nrf2/Gpx4 antioxidant pathway.
- Decreased selenium levels in CRC patients suggest a potential link between selenium status and disease progression.
- Sodium selenite shows promise as a dual-acting agent, functioning as both a nutrient and a pharmacological drug for CRC therapy.
