MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.
| Title: | MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. |
|---|---|
| Authors: | Alborzinia H; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany. hamed.alborzy@gmail.com.; Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany. hamed.alborzy@gmail.com.; Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany. hamed.alborzy@gmail.com.; Flórez AF; Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany.; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.; Kreth S; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Brückner LM; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Yildiz U; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.; Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany.; Gartlgruber M; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Odoni DI; Bioinformatics and Omics Data Analytics, German Cancer Research Center, Heidelberg, Germany.; Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, Augsburg, Germany.; Poschet G; Metabolomics Core Technology Platform, University of Heidelberg, Heidelberg, Germany.; Garbowicz K; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Shao C; Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany.; Klein C; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.; Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany.; Meier J; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.; Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany.; Zeisberger P; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.; Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany.; Nadler-Holly M; Proteome Dynamics, Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Ziehm M; Proteome Dynamics, Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Paul F; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.; Burhenne J; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.; Bell E; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Shaikhkarami M; Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.; Würth R; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.; Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany.; Stainczyk SA; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Wecht EM; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Kreth J; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Büttner M; Metabolomics Core Technology Platform, University of Heidelberg, Heidelberg, Germany.; Ishaque N; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Digital Health Center, Berlin, Germany.; Schlesner M; Bioinformatics and Omics Data Analytics, German Cancer Research Center, Heidelberg, Germany.; Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, Augsburg, Germany.; Nicke B; Target Discovery Technologies, Bayer AG, Berlin, Germany.; Stresemann C; Research & Development, Pharmaceuticals Division, Bayer AG, Berlin, Germany.; Llamazares-Prada M; Division of Cancer Epigenomics, German Cancer Research Center, Member of the German Center for Lung Research, Heidelberg, Germany.; Reiling JH; Translational Research to AdvanCe Therapeutics and Innovation in ONcology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Fischer M; Experimental Pediatric Oncology, Children's Hospital and Center for Molecular Medicine, Medical Faculty, University of Cologne, Cologne, Germany.; Amit I; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.; Selbach M; Proteome Dynamics, Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Charité-Universitätsmedizin Berlin, Berlin, Germany.; Herrmann C; Bioinformatics and Omics Data Analytics, German Cancer Research Center, Heidelberg, Germany.; Health Data Science Unit, Medical Faculty University Heidelberg and BioQuant, Heidelberg, Germany.; Wölfl S; Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.; Henrich KO; Hopp Children's Cancer Center, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.; Höfer T; Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany.; Trumpp A; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.; Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany.; German Cancer Consortium, Heidelberg, Germany.; Westermann F; Hopp Children's Cancer Center, Heidelberg, Germany. f.westermann@dkfz.de.; Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany. f.westermann@dkfz.de. |
| Source: | Nature cancer [Nat Cancer] 2022 Apr; Vol. 3 (4), pp. 471-485. Date of Electronic Publication: 2022 Apr 28. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101761119 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2662-1347 (Electronic) Linking ISSN: 26621347 NLM ISO Abbreviation: Nat Cancer Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Publishing Group, [2020]- |
| MeSH Terms: | Ferroptosis*/genetics ; Neuroblastoma*/genetics; Cysteine/therapeutic use ; Glutathione/therapeutic use ; N-Myc Proto-Oncogene Protein/genetics ; Cell Death ; Child ; Humans |
| Abstract: | 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.; (© 2022. The Author(s).) |
| Comments: | Comment in: Clin Transl Med. 2022 Aug;12(8):e963. doi: 10.1002/ctm2.963.. (PMID: 35908258) |
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| Substance Nomenclature: | 0 (MYCN protein, human); 0 (N-Myc Proto-Oncogene Protein); GAN16C9B8O (Glutathione); K848JZ4886 (Cysteine) |
| Entry Date(s): | Date Created: 20220428 Date Completed: 20220502 Latest Revision: 20240206 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9050595 |
| DOI: | 10.1038/s43018-022-00355-4 |
| PMID: | 35484422 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't