Discovery of a selenium transport protein that regulates ferroptosis sensitivity — Involved in cancer and Alzheimer's disease

A research group led by Assistant Professor Junya Ito and Professor Kiyotaka Nakagawa at the Graduate School of Agricultural Science of Tohoku University and Adjunct Lecturer Eikan Mishima (also Senior Scientist at Helmholtz Munich) at the Graduate School of Medicine of Tohoku University, in collaboration with Helmholtz Munich (Germany), has announced their research results showing that "PRDX6," an antioxidant enzyme, serves as a selenium transport protein and regulates ferroptosis, a lipid peroxidation-dependent cell death associated with oxidative stress. Since ferroptosis is involved in the pathophysiology of neurodegenerative diseases and cancer, the findings are expected to contribute to the development of a new therapeutic strategy for these diseases. The results were published in the December 5 issue of the international journal Molecular Cell.

Ferroptosis is a cell death modality caused by highly reactive lipid radicals (oxidized lipids) induced by iron-mediated lipid peroxidation associated with oxidative stress, a concept that was first proposed in 2012. It has been reported to be involved in the sensitivity of cancer cells to anticancer agents and the pathophysiology of neurodegenerative diseases such as Alzheimer's disease, and its modulation is expected to benefit the treatment of these diseases. For example, cancer cells resistant to anticancer drugs can reportedly be made vulnerable to ferroptosis.

In the human body, selenium itself is highly antioxidative and is used in the synthesis of selenoproteins, which are involved in the regulation of oxidative stress and have selenium at their active centers. Among selenoproteins, GPX4 has been shown to be an enzyme that reduces and detoxifies lipid radicals.

In this study, the research group focused on PRDX6, which, like GPX4, was known to detoxify lipid radicals, and investigated its role. PRDX6 was known to be involved in the ferroptosis susceptibility. First, they generated cancer cells lacking PRDX6 and tried to induce ferroptosis by various inducers. Cell death was induced in PRDX6-deficient cells by all of the inducers at lower concentrations than in normal cells.

To elucidate this mechanism, they investigated the reducing ability (detoxification action) of PRDX6. They reached the unexpected result that its lipid radical reducing ability was markedly lower than that of GPX4. Based on this result, they explored the roles of PRDX6 other than its reducing ability and found that the GPX4 expression was also decreased in cultured PRDX6-deficient cells. Therefore, the relationship between PRDX6 and GPX4 was further investigated.

The results revealed that PRDX6 was an intracellular selenium transport protein. Selenium is difficult to handle because of its extremely high antioxidant capacity, and its level is strictly regulated in living organisms. Thus, selenium must be transported intracellularly in a stable manner. Although the existence of selenium transport proteins has been predicted for a long time, this was the first study to identify an intracellular selenium transport protein.

Furthermore, the in vivo role of PRDX6 was studied in mice. They confirmed that tumor formation by cancer cells lacking PRDX6 was suppressed in mice. In PRDX6-deficient mice, the GPX4 expression in the brain was decreased as was the case in cultured cells lacking PRDX6, confirming its involvement in vivo. The results demonstrated the possibility that PRDX6 is involved in the pathophysiology of neurodegenerative diseases.

Ito said, "Moving forward, I would like to study the effects of PRDX6 deficiency in the brain and see why GPX4 expression is reduced by PRDX6 deficiency. Further, since my research at the Graduate School of Agricultural Science focuses on food functionality and lipid oxidation, I would like to take on the challenge of elucidating whether ferroptosis can be controlled by food ingredients."

Journal Information
Publication: Molecular Cell
Title: PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization
DOI: 10.1016/j.molcel.2024.10.028