MYCN mediates cysteine addiction and sensitizes to ferroptosis
MYCN mediates cysteine addiction and sensitizes to ferroptosis
Abstract Aberrant expression of MYC 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 MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and irondependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically.
Br¨1ckner Lena M.、Kreth Jochen、Poschet Gernot、Henrich Kai-Oliver、B¨1ttner Michael、Nicke Barbara、Selbach Matthias、Alborzinia Hamed、Fl¨?rez Andr¨|s F.、Gartlgruber Moritz、Nadler-Holly Michal、Paul Franziska、Shaikhkarami Marjan、Hartlieb Sabine、Dreidax Daniel、W?lfl Stefan、Westermann Frank、Herrmann Carl、Amit Ido、Ziehm Matthias、H?fer Thomas、Gogolin Sina、Shao Chunxuan、Steinhauser Sebastian、Hess Elisa M.、Bell Emma、Stresemann Carlo、Reiling Jan H.、Fischer Matthias
Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Metabolomics Core Technology Platform, University of HeidelbergDivision of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Metabolomics Core Technology Platform, University of HeidelbergTarget Discovery TechnologiesProteome Dynamics, Max-Delbr¨1ck-Center for Molecular Medicine (MDC)Institute of Pharmacy and Molecular Biotechnology, Heidelberg UniversityDivision of Theoretical Systems Biology, German Cancer Research Center (DKFZ)Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Proteome Dynamics, Max-Delbr¨1ck-Center for Molecular Medicine (MDC)Immunogenomics, Weizmann Institute of ScienceInstitute of Pharmacy and Molecular Biotechnology, Heidelberg UniversityDivision of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Institute of Pharmacy and Molecular Biotechnology, Heidelberg UniversityDivision of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Division of Theoretical Bioinformatics (DKFZ)Immunogenomics, Weizmann Institute of ScienceProteome Dynamics, Max-Delbr¨1ck-Center for Molecular Medicine (MDC)Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ)Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ)Division of Theoretical Bioinformatics (DKFZ)Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ) and Hopp-Children?ˉs Comprehensive Cancer Center at the NCT (KiTZ)Drug Discovery, Pharmaceuticals Oncology IBioMed X Innovation CenterExperimental Pediatric Oncology, Children?ˉs Hospital, and Center of Molecular Medicine (CMMC), Medical Faculty, University of Cologne
肿瘤学生物化学分子生物学
Br¨1ckner Lena M.,Kreth Jochen,Poschet Gernot,Henrich Kai-Oliver,B¨1ttner Michael,Nicke Barbara,Selbach Matthias,Alborzinia Hamed,Fl¨?rez Andr¨|s F.,Gartlgruber Moritz,Nadler-Holly Michal,Paul Franziska,Shaikhkarami Marjan,Hartlieb Sabine,Dreidax Daniel,W?lfl Stefan,Westermann Frank,Herrmann Carl,Amit Ido,Ziehm Matthias,H?fer Thomas,Gogolin Sina,Shao Chunxuan,Steinhauser Sebastian,Hess Elisa M.,Bell Emma,Stresemann Carlo,Reiling Jan H.,Fischer Matthias.MYCN mediates cysteine addiction and sensitizes to ferroptosis[EB/OL].(2025-03-28)[2025-05-09].https://www.biorxiv.org/content/10.1101/2021.08.10.455675.点此复制
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