Cited by 85Ferroptosis and cancer prognosisNeuroblastoma Research and TreatmentsSelenium in Biological Systems
LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma
Open accessAlborzinia, Hamed, Chen, Zhiyi, Yildiz, Umut, Freitas, Florencio Porto, Vogel, Felix C E, Varga, Julianna Patricia, Batani, Jasmin, Bartenhagen, Christoph +25 more·2023·EMBO Molecular Medicine
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.
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LRP8 has been recently shown to affect ferroptosis by regulating the level of selenoprotein GPX4 in cancer cells.
“LRP8 has been recently shown to affect ferroptosis by regulating the level of selenoprotein GPX4 in cancer cells (54–56).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [56]
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- Authors
- Alborzinia, H., Chen, Z., Yildiz, U., Freitas, F. P., Vogel, F. C. E., Varga, J. P., Batani, J., Bartenhagen, C., Schmitz, W., Büchel, G., Michalke, B., Zheng, J., Meierjohann, S., Girardi, E., Espinet, E., Flórez, A. F., dos Santos, A. F., Aroua, N., Cheytan, T., Haenlin, J., Schlicker, L., Xavier da Silva, T. N., Przybylla, A., Zeisberger, P., Superti‐Furga, G., Eilers, M., Conrad, M., Fabiano, M., Schweizer, U., Fischer, M., Schulze, A., Trumpp, A., & Friedmann Angeli, J. P.
- Affiliations
- German Cancer Research Center (DE)
- University of Würzburg (DE)
- European Molecular Biology Organization (DE)
- University of Cologne (DE)
- Universitätsklinikum Würzburg (DE)
- Helmholtz Munich (DE)
- Austrian Academy of Sciences (AT)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Harvard University (US)
- University of Bonn (DE)
- Corresponding author
- Alborzinia, Hamed
- Trumpp, Andreas
- ORCID
- Alborzinia, Hamed
- Chen, Zhiyi
- Yildiz, Umut
- Freitas, Florencio Porto
- Vogel, Felix C E
- Varga, Julianna Patricia
- Bartenhagen, Christoph
- Schmitz, Werner
- Büchel, Gabriele
- Michalke, Bernhard
- Zheng, Jashuo
- Meierjohann, Svenja
- Girardi, Enrico
- Espinet, Elisa
- Flórez, Andrés F
- Aroua, Nesrine
- Cheytan, Tasneem
- Schlicker, Lisa
- Xavier da Silva, Thamara N
- Superti‐Furga, Giulio
- Eilers, Martin
- Conrad, Marcus
- Fabiano, Marietta
- Schweizer, Ulrich
- Fischer, Matthias
- Schulze, Almut
- Trumpp, Andreas
- Friedmann Angeli, José Pedro
- Venue
- EMBO Molecular Medicine
- Published
- 2023-07-12
- Volume
- 15
- Issue
- 8
- Pages
- e18014-e18014
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC10405063
- OpenAlex
- W4383999429
- Cited by
- 85
- References
- 48
- Citations by year
- 2026: 29 · 2025: 27 · 2024: 26 · 2023: 3
- FWCI
- 15.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Alexander von Humboldt‐Stiftung
- Austrian Academy of Science
- Bundesministerium für Bildung und Forschung (01ZX1603, 01ZX1607)
- Deutsche Forschungsgemeinschaft (FR 3746/3‐1, FR 3746/6‐1, INST 269/886‐1, FOR2674, 1926/2‐1, 6984/1‐1, SPP2306, SCHU 2670/4‐1, SCHU 2670/2‐2 (FOR2314), CO 297/9‐1, CO 291/7‐1, CO 291/10‐1, FOR2314, SFB1399, CC873)
- Deutsche Krebshilfe (70113450)
- Deutschen Konsortium für Translationale Krebsforschung
- Dietmar Hopp Stiftung
- EC | European Research Council (GA 884754, 695214)
- EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska‐Curie Actions (MSCA‐IF‐2014‐661491)
- Förderverein für Krebskranke Kinder
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Keywords
- LRP8, ferroptosis, MYCN-amplified neuroblastoma, selenoprotein P, GPX4, selenium metabolism, system xc-, CRISPR activation screen, orthotopic xenograft
- MeSH terms
- N-Myc Proto-Oncogene Protein, Ferroptosis, Animals, Humans, Neuroblastoma, Selenocysteine, LDL-Receptor Related Proteins, Cell Line, Tumor
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