LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma
© 2023 The Authors. Published under the terms of the CC BY 4.0 license..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
EMBO molecular medicine - 15(2023), 8 vom: 07. Aug., Seite e18014 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 09.08.2023 Date Revised 09.08.2023 published: Print-Electronic GEO: GSE210762 Citation Status MEDLINE |
|---|
| doi: |
10.15252/emmm.202318014 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359367178 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359367178 | ||
| 003 | DE-627 | ||
| 005 | 20231226080723.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.15252/emmm.202318014 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1197.xml |
| 035 | |a (DE-627)NLM359367178 | ||
| 035 | |a (NLM)37435859 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Alborzinia, Hamed |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.08.2023 | ||
| 500 | |a Date Revised 09.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a GEO: GSE210762 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Published under the terms of the CC BY 4.0 license. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a ferroptosis | |
| 650 | 4 | |a neuroblastoma | |
| 650 | 4 | |a selenocysteine | |
| 650 | 4 | |a selenoprotein | |
| 650 | 4 | |a synthetic lethality | |
| 650 | 7 | |a low density lipoprotein receptor-related protein 8 |2 NLM | |
| 650 | 7 | |a MYCN protein, human |2 NLM | |
| 650 | 7 | |a N-Myc Proto-Oncogene Protein |2 NLM | |
| 650 | 7 | |a Selenocysteine |2 NLM | |
| 650 | 7 | |a 0CH9049VIS |2 NLM | |
| 700 | 1 | |a Chen, Zhiyi |e verfasserin |4 aut | |
| 700 | 1 | |a Yildiz, Umut |e verfasserin |4 aut | |
| 700 | 1 | |a Freitas, Florencio Porto |e verfasserin |4 aut | |
| 700 | 1 | |a Vogel, Felix C E |e verfasserin |4 aut | |
| 700 | 1 | |a Varga, Julianna Patricia |e verfasserin |4 aut | |
| 700 | 1 | |a Batani, Jasmin |e verfasserin |4 aut | |
| 700 | 1 | |a Bartenhagen, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Schmitz, Werner |e verfasserin |4 aut | |
| 700 | 1 | |a Büchel, Gabriele |e verfasserin |4 aut | |
| 700 | 1 | |a Michalke, Bernhard |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Jashuo |e verfasserin |4 aut | |
| 700 | 1 | |a Meierjohann, Svenja |e verfasserin |4 aut | |
| 700 | 1 | |a Girardi, Enrico |e verfasserin |4 aut | |
| 700 | 1 | |a Espinet, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Flórez, Andrés F |e verfasserin |4 aut | |
| 700 | 1 | |a Dos Santos, Ancely Ferreira |e verfasserin |4 aut | |
| 700 | 1 | |a Aroua, Nesrine |e verfasserin |4 aut | |
| 700 | 1 | |a Cheytan, Tasneem |e verfasserin |4 aut | |
| 700 | 1 | |a Haenlin, Julie |e verfasserin |4 aut | |
| 700 | 1 | |a Schlicker, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Xavier da Silva, Thamara N |e verfasserin |4 aut | |
| 700 | 1 | |a Przybylla, Adriana |e verfasserin |4 aut | |
| 700 | 1 | |a Zeisberger, Petra |e verfasserin |4 aut | |
| 700 | 1 | |a Superti-Furga, Giulio |e verfasserin |4 aut | |
| 700 | 1 | |a Eilers, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Conrad, Marcus |e verfasserin |4 aut | |
| 700 | 1 | |a Fabiano, Marietta |e verfasserin |4 aut | |
| 700 | 1 | |a Schweizer, Ulrich |e verfasserin |4 aut | |
| 700 | 1 | |a Fischer, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Schulze, Almut |e verfasserin |4 aut | |
| 700 | 1 | |a Trumpp, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Friedmann Angeli, José Pedro |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t EMBO molecular medicine |d 2009 |g 15(2023), 8 vom: 07. Aug., Seite e18014 |w (DE-627)NLM192618962 |x 1757-4684 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2023 |g number:8 |g day:07 |g month:08 |g pages:e18014 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.15252/emmm.202318014 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2023 |e 8 |b 07 |c 08 |h e18014 | ||