2. Academic Validation
  3. MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

  • Cell Death Dis. 2021 May 19;12(6):511. doi: 10.1038/s41419-021-03790-w.
Yuxiong Lu  # 1 2,  Qing Yang  # 3,  Yubin Su  # 4,  Yin Ji  # 5,  Guobang Li 3,  Xianzhi Yang 3,  Liyan Xu 3,  Zhaoliang Lu 1,  Jiajun Dong 6,  Yi Wu 6,  Jin-Xin Bei 2 7,  Chaoyun Pan 3 8,  Xiaoqiong Gu 9,  Bo Li 2 3 7 8
Affiliations

Affiliations

  • 1 Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 4 Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China.
  • 5 State Key Laboratory of Translational Medicine and Innovative Drug Development, Simcere Diagnostics Co., Ltd., Nanjing, China.
  • 6 Department of Neurosurgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital, Sun Yat-sen University, Jiangmen, China.
  • 7 Center for Precision Medicine, Sun Yat-sen University, Guangzhou, China.
  • 8 RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 9 Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. guxiaoqiong@gwcmc.org.
  • # Contributed equally.
PMID: 34011924 DOI: 10.1038/s41419-021-03790-w
Abstract

MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates Ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting Ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes Transferrin Receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and Ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(-) for glutathione synthesis, both of which contribute to Ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo Ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting Ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.

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