The Dual Regulation Effects of ESR1/NEDD4L on SLC7A11 in Breast Cancer Under Ionizing Radiation

Abstract

Radiotherapy is one of the most important treatments for breast cancer. Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, whether ionizing radiation (IR) could induce ferroptosis in breast cancer and how it works remain unknown. Bioinformatics analysis were performed to screen ferroptosis-related genes differentially expressed in breast tumor tissue and normal tissue. Then, breast cancer cell lines with different estrogen receptor (ER) phenotypes were used for studies in vitro, including ER-positive (MCF-7 and ZR-75-1) and ER-negative (MDA-MB-231) cells. The dynamic changes of mRNA and protein levels were examined after x-ray of 8 Gy by qRT-PCR and Western blotting, respectively. Immunoprecipitation (IP) was used to explore the interaction between proteins. Luciferase assay was used to analyze the transcriptional regulation effect of ESR1 on SLC7A11. BODIPY C11 and trypan blue dyes were used to determine lipid peroxidation and cell death, respectively. The result showed that the ferroptosis-related gene SLC7A11 was higher in breast cancer tissues compared with normal tissues and associated with poor survival. A positive correlation exists between ESR1 and SLC7A11 expression. ESR1 promoted SLC7A11 expression at the early stage after IR. ESR1/SLC7A11 knockdown significantly enhanced IR-induced ferroptosis in ER-positive cells. At 12 h after IR, the IP data showed the interaction between E3 ubiquitin ligase NEDD4L and SLC7A11 increased, followed by the ubiquitylation and degradation of SLC7A11. Thus, SLC7A11 expression was regulated by both ESR1 and NEDD4L, in opposite ways. For the first time, we elucidated that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells, which provides novel insight into the guidance of clinical treatment of breast cancer.

NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation

“…An in vitro study showed that NEDD4L inhibits GC proliferation by promoting the ferroptosis of GCs. Consistent with our results, Rui Liu et al found that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells ( 27 ). This work, as well as other studies, further confirms that the regulation of NEDD4L on cell proliferation is a complex and diverse process.…”

Solute Carrier Family 7 Member 11 (SLC7A11) is a Potential Prognostic Biomarker in Uterine Corpus Endometrial Carcinoma

“… 16 , 18 , 47 , 48 In addition, SLC7A11 imports extracellular cystine into cells to promote glutathione synthesis, thus inhibiting ferroptosis. 49 It was reported that ferroptosis was closely related to several endometrial diseases, such as endometriosis, 50 , 51 repeated implantation failure, 52 and endometrial hyperplasia, 53 and it can act as a therapeutic target for these diseases. Notably, the abnormal biological behaviors of EC patients are tightly associated with the occurrence of adenomyosis and endometriosis.…”

“…SLC7A11 protein is an important cystine/glutamate transporter that is highly conserved across eukaryotes. 49 Furthermore, the SLC7A11 protein possesses the most conserved region (TIGR00911) of the human solute carrier (SLC) family proteins, which plays an important role in the transportation and binding of proteins, amino acids, peptides and amines. Our findings also revealed that the SLC7A11 protein was localized in the vesicles of human cells.…”

Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy

“… ESR1/SLC7A11 knockdown significantly promotes radiation-induced ferroptosis in ER-positive breast cancer cells. [ 190 ] Sculponeatin Sculponeatin is a diterpenoid extracted from Isodon sculponeatus. Sculponeatin reduced the expression of ETS1 which is an inducer of SLC7A11-dependent ferroptosis in breast cancer.…”