Alborzinia, Hamed, Florez, Andres F., Kreth, Sina, Brueckner, Lena M., Yildiz, Umut ORCID: 0000-0002-7175-362X, Gartlgruber, Moritz, Odoni, Dorett, I, Poschet, Gernot ORCID: 0000-0002-5344-0865, Garbowicz, Karolina, Shao, Chunxuan, Klein, Corinna, Meier, Jasmin, Zeisberger, Petra, Nadler-Holly, Michal, Ziehm, Matthias ORCID: 0000-0001-7074-4054, Paul, Franziska, Burhenne, Juergen, Bell, Emma, Shaikhkarami, Marjan, Wuerth, Roberto, Stainczyk, Sabine A., Wecht, Elisa M., Kreth, Jochen, Buettner, Michael, Ishaque, Naveed ORCID: 0000-0002-8426-901X, Schlesner, Matthias, Nicke, Barbara, Stresemann, Carlo, Llamazares-Prada, Maria, Reiling, Jan H., Fischer, Matthias, Amit, Ido, Selbach, Matthias ORCID: 0000-0003-2454-8751, Herrmann, Carl, Woelfl, Stefan, Henrich, Kai-Oliver, Hoefer, Thomas, Trumpp, Andreas and Westermann, Frank (2022). MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat. Cancer, 3 (4). S. 471 - 502. BERLIN: NATURE PORTFOLIO. ISSN 2662-1347

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Abstract

Alborzinia et al. report that MYCN-amplified neuroblastoma undergoes ferroptosis in the absence of intracellular cysteine, suggesting a combination of cysteine depletion and concomitant GPX4 inactivation as a potential therapeutic approach. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Alborzinia, HamedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florez, Andres F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreth, SinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brueckner, Lena M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yildiz, UmutUNSPECIFIEDorcid.org/0000-0002-7175-362XUNSPECIFIED
Gartlgruber, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odoni, Dorett, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poschet, GernotUNSPECIFIEDorcid.org/0000-0002-5344-0865UNSPECIFIED
Garbowicz, KarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shao, ChunxuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meier, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeisberger, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nadler-Holly, MichalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziehm, MatthiasUNSPECIFIEDorcid.org/0000-0001-7074-4054UNSPECIFIED
Paul, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burhenne, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bell, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shaikhkarami, MarjanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wuerth, RobertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stainczyk, Sabine A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wecht, Elisa M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreth, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ishaque, NaveedUNSPECIFIEDorcid.org/0000-0002-8426-901XUNSPECIFIED
Schlesner, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nicke, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stresemann, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Llamazares-Prada, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiling, Jan H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amit, IdoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Selbach, MatthiasUNSPECIFIEDorcid.org/0000-0003-2454-8751UNSPECIFIED
Herrmann, CarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woelfl, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henrich, Kai-OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoefer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trumpp, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-694211
DOI: 10.1038/s43018-022-00355-4
Journal or Publication Title: Nat. Cancer
Volume: 3
Number: 4
Page Range: S. 471 - 502
Date: 2022
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2662-1347
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL-DEATH; TRANSSULFURATION PATHWAY; EXPRESSION; ACTIVATION; GLUTAMINOLYSIS; PROLIFERATION; GLUTATHIONE; MECHANISM; SCALE; ATF4Multiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69421

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