LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma

Abstract

Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR‐activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN‐amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc−. The identification of LRP8 as a specific vulnerability of MYCN‐amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet‐unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high‐risk neuroblastoma and potentially other MYCN‐amplified entities.

Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis

“…However, it remains to be elucidated which of those pathways are conserved in specific tissues and cell types. We and others have previously showed that selenium deprivation and uptake inhibition sensitizes to ferroptosis selectively when cells are cultured at low density 23,24,34 . Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the seeding density positively regulates the expression of genes involved in fatty acid synthesis and desaturation (i.e.…”

“…Indeed, GPX4 inhibition in combination with immunotherapy showed promising results in murine models of TNBC 42 . While selenium-deprived diets have not been tested in breast cancer models, Eagle et al showed a therapeutic effect of selenium deprivation in leukaemia models, while Alborzinia et al inhibited cellular selenoprotein P uptake to decrease the expression of selenoproteins and induce ferroptosis in neuroblastoma 22,24 .…”

“…The supplementation with an excess of selenium and the inhibition of Sec-tRNA sec synthesis can both lead to the accumulation of reactive selenium species toxic to cancer cells 20,21 . On the other hand, selenium deprivation has been shown to induce ferroptosis in cells from breast cancer, acute myeloid leukaemia, and neuroblastoma [22][23][24] . Several pre-clinical and clinical studies assessed selenium supplementation as an antioxidant cancer-preventive intervention and selenium is frequently found in fortified food, and multivitamin/multimineral supplements 25,26 .…”

PSL Chemical Biology Symposia: Recent Progress in Ferroptosis

“…Recent studies have identified the LRP8/SELENOP axis as responsible for selenocysteine uptake inside the cell and SCLY for its recycling, therefore the inhibition of this pathway can promote ferroptosis. [20] Angeli and coworkers also identified a new regulator of selenium metabolism as a regulator of ferroptosis, which also appears to act by maintaining the stability of GPX4. It exhibits a very stable sulfenic acid group that interacts with hydrogen selenide anion to provide a new potential selenium donor.…”

“…Selenium can be absorbed as inorganic form (SeO 3 2− ) and organic forms (selenocysteine). Recent studies have identified the LRP8/SELENOP axis as responsible for selenocysteine uptake inside the cell and SCLY for its recycling, therefore the inhibition of this pathway can promote ferroptosis [20] . Angeli and coworkers also identified a new regulator of selenium metabolism as a regulator of ferroptosis, which also appears to act by maintaining the stability of GPX4.…”