MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis
Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cy...
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
28 April 2022
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| In: |
Nature cancer
Year: 2022, Jahrgang: 3, Heft: 4, Pages: 471-485 |
| ISSN: | 2662-1347 |
| DOI: | 10.1038/s43018-022-00355-4 |
| Online-Zugang: | Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1038/s43018-022-00355-4 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s43018-022-00355-4 
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| Verfasserangaben: | Hamed Alborzinia, Andrés F. Flórez, Sina Kreth, Lena M. Brückner, Umut Yildiz, Moritz Gartlgruber, Dorett I. Odoni, Gernot Poschet, Karolina Garbowicz, Chunxuan Shao, Corinna Klein, Jasmin Meier, Petra Zeisberger, Michal Nadler-Holly, Matthias Ziehm, Franziska Paul, Jürgen Burhenne, Emma Bell, Marjan Shaikhkarami, Roberto Würth, Sabine A. Stainczyk, Elisa M. Wecht, Jochen Kreth, Michael Büttner, Naveed Ishaque, Matthias Schlesner, Barbara Nicke, Carlo Stresemann, María Llamazares-Prada, Jan H. Reiling, Matthias Fischer, Ido Amit, Matthias Selbach, Carl Herrmann, Stefan Wölfl, Kai-Oliver Henrich, Thomas Höfer, Andreas Trumpp and Frank Westermann |
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| 245 | 1 | 0 | |a MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis |c Hamed Alborzinia, Andrés F. Flórez, Sina Kreth, Lena M. Brückner, Umut Yildiz, Moritz Gartlgruber, Dorett I. Odoni, Gernot Poschet, Karolina Garbowicz, Chunxuan Shao, Corinna Klein, Jasmin Meier, Petra Zeisberger, Michal Nadler-Holly, Matthias Ziehm, Franziska Paul, Jürgen Burhenne, Emma Bell, Marjan Shaikhkarami, Roberto Würth, Sabine A. Stainczyk, Elisa M. Wecht, Jochen Kreth, Michael Büttner, Naveed Ishaque, Matthias Schlesner, Barbara Nicke, Carlo Stresemann, María Llamazares-Prada, Jan H. Reiling, Matthias Fischer, Ido Amit, Matthias Selbach, Carl Herrmann, Stefan Wölfl, Kai-Oliver Henrich, Thomas Höfer, Andreas Trumpp and Frank Westermann |
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| 520 | |a Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors. | ||
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