ESR1 inhibits ionizing radiation-induced ferroptosis in breast cancer cells via the NEDD4L/CD71 pathway.

Abstract

Ferroptosis is the name given to the type of non-apoptotic cell death that is caused by iron accumulation and subsequent lipid peroxidation. However, how ionizing radiation (IR)-induced ferroptosis is regulated in estrogen receptor-positive (ER+) breast cancer cells remains unclear. To attempt to resolve this issue, bioinformatics analysis was performed to evaluate the prognostic value of estrogen receptor 1 (ESR1) in breast cancer tissues. A total of four breast cancer cell lines and an MCF10A non-malignant counterpart were used. Western blotting was used to analyze the levels of protein expression, whereas immunoprecipitation (IP) and ubiquitination experiments were used to test protein binding and ubiquitination levels, respectively. Flow cytometry was subsequently used to analyze cell death and lipid peroxidation levels. The results showed that a high expression level of ESR1 was significantly correlated with poor overall survival in breast cancer. ESR1 knockdown significantly enhanced IR-induced ferroptosis and increased the CD71 protein level. The IP results showed that ESR1 enhanced the binding of the E3 ubiquitin ligase NEDD4L to CD71, promoting the ubiquitination and degradation of CD71, suggesting that CD71 expression was regulated by both ESR1 and NEDD4L. Taken together, the findings in the present study have demonstrated a regulatory relationship between ESR1 and NEDD4L/CD71 in IR-induced ferroptosis. In addition, the ESR1/NEDD4L/CD71 axis may be a potential target for the radiotherapy of breast cancer.

• Authors: Lin Liu, Chen Zhang, Shugen Qu, Rui Liu, Huajian Chen, Zhenzhen Liang, Zhujun Tian, Lan Li, Shumei Ma, Xiaodong Liu
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 725 Pg. 109299 (08 15 2022) ISSN: 1096-0384 [Electronic] United States
• PMID: 35613689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, CD
• CD71 antigen
• ESR1 protein, human
• Estrogen Receptor alpha
• Receptors, Transferrin
• Nedd4 Ubiquitin Protein Ligases
• Nedd4L protein, human

Topics

• Antigens, CD (metabolism)
• Breast Neoplasms (genetics, metabolism, radiotherapy)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Ferroptosis
• Humans
• MCF-7 Cells
• Nedd4 Ubiquitin Protein Ligases (metabolism)
• Radiation, Ionizing
• Receptors, Transferrin (metabolism)