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.
Highlights
Breast cancer is a complex and clinically heterogeneous disease
Our study found that solute carrier family 7 member 11 (SLC7A11) was correlative to survival in breast cancer and high expression implied poor prognosis
Our research suggested that ferroptosis occupies a very important position in ionizing radiation (IR)-induced cell death in ERpositive cell lines
Summary
Breast cancer is a complex and clinically heterogeneous disease. Similar clinicopathologic characteristics and histologic types may have different clinical course and survival rates, and distinct molecular subtypes of tumors are inextricably bound up with clinical outcomes (Kumar Atri et al, 2017; Lian et al, 2017). Ferroptosis is a novel type of programmed cell death distinct from apoptosis, necrosis, and autophagy, which is an iron-dependent form of regulated cell death involving accumulation of reactive oxygen species (ROS) and overwhelming lipid peroxidation (Stockwell et al, 2017). IR induces ferroptosis in cancer patients and improves the therapeutic effects and survival of radiation therapy (Wu et al, 2020a; Lei et al, 2020). The mechanisms for IR-induced ferroptosis and regulation in breast cancer cells remain largely unknown. We designed a systematic study to elucidate the underlying mechanisms of radio-resistance in ER-positive breast cells and managed to improve radiation killing effect through targeted intervention of IR-induced ferroptosis
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