MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma
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 ce...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-05-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03790-w |
| _version_ | 1819085572831969280 |
|---|---|
| author | Yuxiong Lu Qing Yang Yubin Su Yin Ji Guobang Li Xianzhi Yang Liyan Xu Zhaoliang Lu Jiajun Dong Yi Wu Jin-Xin Bei Chaoyun Pan Xiaoqiong Gu Bo Li |
| author_facet | Yuxiong Lu Qing Yang Yubin Su Yin Ji Guobang Li Xianzhi Yang Liyan Xu Zhaoliang Lu Jiajun Dong Yi Wu Jin-Xin Bei Chaoyun Pan Xiaoqiong Gu Bo Li |
| author_sort | Yuxiong Lu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T21:06:30Z |
| format | Article |
| id | doaj.art-adcfc95ceca148b8bd3fc5e0cf04bd0a |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-21T21:06:30Z |
| publishDate | 2021-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-adcfc95ceca148b8bd3fc5e0cf04bd0a2022-12-21T18:50:17ZengNature Publishing GroupCell Death and Disease2041-48892021-05-0112611410.1038/s41419-021-03790-wMYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastomaYuxiong Lu0Qing Yang1Yubin Su2Yin Ji3Guobang Li4Xianzhi Yang5Liyan Xu6Zhaoliang Lu7Jiajun Dong8Yi Wu9Jin-Xin Bei10Chaoyun Pan11Xiaoqiong Gu12Bo Li13Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityKey Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan UniversityState Key Laboratory of Translational Medicine and Innovative Drug Development, Simcere Diagnostics Co., Ltd.Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityClinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Neurosurgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital, Sun Yat-sen UniversityDepartment of Neurosurgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital, Sun Yat-sen UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen UniversityClinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-sen UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterAbstract 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.https://doi.org/10.1038/s41419-021-03790-w |
| spellingShingle | Yuxiong Lu Qing Yang Yubin Su Yin Ji Guobang Li Xianzhi Yang Liyan Xu Zhaoliang Lu Jiajun Dong Yi Wu Jin-Xin Bei Chaoyun Pan Xiaoqiong Gu Bo Li MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma Cell Death and Disease |
| title | MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma |
| title_full | MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma |
| title_fullStr | MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma |
| title_full_unstemmed | MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma |
| title_short | MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma |
| title_sort | mycn mediates tfrc dependent ferroptosis and reveals vulnerabilities in neuroblastoma |
| url | https://doi.org/10.1038/s41419-021-03790-w |
| work_keys_str_mv | AT yuxionglu mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT qingyang mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT yubinsu mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT yinji mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT guobangli mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT xianzhiyang mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT liyanxu mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT zhaolianglu mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT jiajundong mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT yiwu mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT jinxinbei mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT chaoyunpan mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT xiaoqionggu mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma AT boli mycnmediatestfrcdependentferroptosisandrevealsvulnerabilitiesinneuroblastoma |