Kyoto University led group discovers new metabolic regulator of selenium, an "essential element for life"

Selenium, atomic number 34, is an essential element for life and is involved in antioxidant, detoxification, immune enhancement, and other biological functions. A research group led by Program-specific Senior Lecturer Hiroaki Fujita and Professor Kazuhiro Iwai of Kyoto University Graduate School of Medicine, Professor Takaaki Akaike of Tohoku University, and Professor Yasumitsu Ogra of Chiba University has discovered a new regulator of selenium metabolism, PRDX6. They found that the PRDX6 expression was increased in a variety of cancer tissues and that cancer patients with high PRDX6 expression have a poor prognosis. Fujita said, "The development of PRDX6 inhibitors may pave the way to anticancer drugs that induce ferroptosis (cell death) of cancer cells without side effects. We are currently working on artificial intelligence drug discovery with a pharmaceutical laboratory at Kyoto University." The work was published in Nature Structural & Molecular Biology.

Selenium, as the 21st amino acid selenocysteine, is specifically incorporated into various antioxidant enzymes to exert antioxidant, anti-inflammatory and detoxification functions. A selenium deficiency can lead to decreased immune and sperm function, thyroiditis, and other disorders, while problems associated with selenium excess include dermatitis, hair loss, and increased risk for cancer and diabetes.

The research group has been studying ferroptosis, a form of cell death triggered by iron-induced oxidation of cell membranes. Intracellular iron levels are strictly regulated by the sensor molecule FBXL5. They created FBXL5-deficient cells and found that ferroptosis could be induced simply by adding iron to these cells. To explore this mechanism, they performed a large-scale screening for regulators in cells lacking all genes. As a result, they succeeded in identifying several ferroptosis regulators. The regulators include multiple selenoprotein synthesis factors. In particular, PRDX6 was identified as one of the most potent factors. Although the existence of PRDX6 was known, its function largely remained unknown. In PRDX6-deficient cells, the expression of the selenoprotein GPX4, an important regulator of ferroptosis, was reduced, and cell death was induced by iron addition alone.

Investigation into the mechanism of selenoprotein synthesis by PRDX6 revealed that PRDX6 increases the efficiency of intracellular selenium utilization and promotes selenoprotein synthesis. Previously, selenium was thought to be efficiently utilized with the aid of intracellular selenium transport proteins because the element selenium is highly reactive and has an extremely low intracellular level. The group analyzed PRDX6 assuming that it might be an unidentified selenium transport protein and found that PRDX6 is a selenium transport protein. Selenium is added to PRDX6 and transported to the selenoprotein synthesis factor.

Meanwhile, antioxidative selenoproteins are expressed at elevated levels in cancer cells and are important for cancer cell survival. They measured the PRDX6 expression levels in cells from cancer patients and found that PRDX6 expression was increased in various cancer tissues. Furthermore, they showed that cancer patients with high PRDX6 expression had a poor prognosis. GPX4 is a potential target for anticancer drugs that induce ferroptosis in cancer cells, but GPX4-knockout mice are nonviable. On the other hand, PRDX6-knockout mice are viable, raising hopes that PRDX6 may be validated as a new target for anticancer drugs.

Iwai said, "When PRDX6 is lost, selenium cannot be used properly, but GPX4 is still produced, although in a small amount. Therefore, if a PRDX6 inhibitor could be developed, it would be a low-toxic anticancer agent. The 5-year survival rates for many cancers have improved dramatically over the past few decades, but the rate for pancreatic cancer has not changed at all. I really hope that this discovery will bring good news to those who have pancreatic cancer."

Journal Information
Publication: Nature Structural & Molecular Biology
Title: PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis
DOI: 10.1038/s41594-024-01329-z