MYCN-Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis
| Autor: | Benjamin R. Belvin, Bin Hu, Madhavi Puchalapalli, Richard Kurupi, Kimberly Swift, Jinyang Cai, Sivapriya Ramamoorthy, Anthony C. Faber, Carter K. Fairchild, Sheeba Jacob, Janina P. Lewis, Mayuri Shende, Sosipatros A. Boikos, John Glod, Mikhail G. Dozmorov, Colin M. Coon, Jennifer E. Koblinski, Krista M. Powell, Konstantinos V. Floros |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Cancer Research Reactive oxygen species Auranofin Oncogene Transferrin receptor Glutathione medicine.disease Article Deferoxamine 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Oncology chemistry 030220 oncology & carcinogenesis Neuroblastoma Cancer research medicine Receptor neoplasms medicine.drug |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-20-1641 |
| Popis: | MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer–related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. Significance: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma. |
| Databáze: | OpenAIRE |
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