Selenium Induces Ferroptosis in Colorectal Cancer Cells via Direct Interaction with Nrf2 and Gpx4

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.