A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to Ferroptosis
Ferroptosis, an iron-dependent form of programmed cell death, has excellent potential as an anti-cancer therapeutic strategy in different types of tumors, especially in RAS-mutated ones. However, the function of ferroptosis for inhibiting neuroblastoma, a common child malignant tumor with minimal tr...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/16/8898 |
| _version_ | 1797523515080966144 |
|---|---|
| author | Ruiqing Lu Yinan Jiang Xianxin Lai Shujie Liu Litao Sun Zhong-Wei Zhou |
| author_facet | Ruiqing Lu Yinan Jiang Xianxin Lai Shujie Liu Litao Sun Zhong-Wei Zhou |
| author_sort | Ruiqing Lu |
| collection | DOAJ |
| description | Ferroptosis, an iron-dependent form of programmed cell death, has excellent potential as an anti-cancer therapeutic strategy in different types of tumors, especially in RAS-mutated ones. However, the function of ferroptosis for inhibiting neuroblastoma, a common child malignant tumor with minimal treatment, is unclear. This study investigated the anti-cancer function of ferroptosis inducer Erastin or RSL3 in neuroblastoma N2A cells. Our results show that Erastin or RSL3 induces ROS level and cell death and, therefore, reduces the viability of RAS-proficient N2A cells. Importantly, inhibitors to ferroptosis, but not apoptosis, ameliorate the high ROS level and viability defect in Erastin- or RSL3-treated cells. In addition, our data also show that N2A cells are much more sensitive to ferroptosis inducers than primary mouse cortical neural stem cells (NSCs) or neurons. Moreover, a higher level of ROS and PARylation is evidenced in N2A, but not NSCs. Mechanically, ferritin heavy chain 1 (<i>Fth</i>), the ferroxidase function to oxidate redox-active Fe<sup>2+</sup> to redox-inactive Fe<sup>3+</sup>, is likely responsible for the hypersensitivity of N2A to ferroptosis induction since its expression is lower in N2A compared to NSCs; ectopic expression of <i>Fth</i> reduces ROS levels and cell death, and induces expression of GPX4 and cell viability in N2A cells. Most importantly, neuroblastoma cell lines express a significantly low level of <i>Fth</i> than almost all other types of cancer cell lines. All these data suggest that Erastin or RSL3 induce ferroptosis cell death in neuroblastoma N2A cells, but not normal neural cells, regardless of RAS mutations, due to inadequate FTH. This study, therefore, provides new evidence that ferroptosis could be a promising therapeutic target for neuroblastoma. |
| first_indexed | 2024-03-10T08:44:05Z |
| format | Article |
| id | doaj.art-9cc8d5cb90d645d3928acd40ac4c83e0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:44:05Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9cc8d5cb90d645d3928acd40ac4c83e02023-11-22T08:02:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216889810.3390/ijms22168898A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to FerroptosisRuiqing Lu0Yinan Jiang1Xianxin Lai2Shujie Liu3Litao Sun4Zhong-Wei Zhou5School of Medicine, Sun Yat-Sen University, Shenzhen 518107, ChinaSchool of Medicine, Sun Yat-Sen University, Shenzhen 518107, ChinaSchool of Medicine, Sun Yat-Sen University, Shenzhen 518107, ChinaSchool of Medicine, Sun Yat-Sen University, Shenzhen 518107, ChinaSchool of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, ChinaSchool of Medicine, Sun Yat-Sen University, Shenzhen 518107, ChinaFerroptosis, an iron-dependent form of programmed cell death, has excellent potential as an anti-cancer therapeutic strategy in different types of tumors, especially in RAS-mutated ones. However, the function of ferroptosis for inhibiting neuroblastoma, a common child malignant tumor with minimal treatment, is unclear. This study investigated the anti-cancer function of ferroptosis inducer Erastin or RSL3 in neuroblastoma N2A cells. Our results show that Erastin or RSL3 induces ROS level and cell death and, therefore, reduces the viability of RAS-proficient N2A cells. Importantly, inhibitors to ferroptosis, but not apoptosis, ameliorate the high ROS level and viability defect in Erastin- or RSL3-treated cells. In addition, our data also show that N2A cells are much more sensitive to ferroptosis inducers than primary mouse cortical neural stem cells (NSCs) or neurons. Moreover, a higher level of ROS and PARylation is evidenced in N2A, but not NSCs. Mechanically, ferritin heavy chain 1 (<i>Fth</i>), the ferroxidase function to oxidate redox-active Fe<sup>2+</sup> to redox-inactive Fe<sup>3+</sup>, is likely responsible for the hypersensitivity of N2A to ferroptosis induction since its expression is lower in N2A compared to NSCs; ectopic expression of <i>Fth</i> reduces ROS levels and cell death, and induces expression of GPX4 and cell viability in N2A cells. Most importantly, neuroblastoma cell lines express a significantly low level of <i>Fth</i> than almost all other types of cancer cell lines. All these data suggest that Erastin or RSL3 induce ferroptosis cell death in neuroblastoma N2A cells, but not normal neural cells, regardless of RAS mutations, due to inadequate FTH. This study, therefore, provides new evidence that ferroptosis could be a promising therapeutic target for neuroblastoma.https://www.mdpi.com/1422-0067/22/16/8898FTHROSferroptosisneuroblastoma |
| spellingShingle | Ruiqing Lu Yinan Jiang Xianxin Lai Shujie Liu Litao Sun Zhong-Wei Zhou A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to Ferroptosis International Journal of Molecular Sciences FTH ROS ferroptosis neuroblastoma |
| title | A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to Ferroptosis |
| title_full | A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to Ferroptosis |
| title_fullStr | A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to Ferroptosis |
| title_full_unstemmed | A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to Ferroptosis |
| title_short | A Shortage of FTH Induces ROS and Sensitizes RAS-Proficient Neuroblastoma N2A Cells to Ferroptosis |
| title_sort | shortage of fth induces ros and sensitizes ras proficient neuroblastoma n2a cells to ferroptosis |
| topic | FTH ROS ferroptosis neuroblastoma |
| url | https://www.mdpi.com/1422-0067/22/16/8898 |
| work_keys_str_mv | AT ruiqinglu ashortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT yinanjiang ashortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT xianxinlai ashortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT shujieliu ashortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT litaosun ashortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT zhongweizhou ashortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT ruiqinglu shortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT yinanjiang shortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT xianxinlai shortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT shujieliu shortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT litaosun shortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis AT zhongweizhou shortageoffthinducesrosandsensitizesrasproficientneuroblastoman2acellstoferroptosis |