Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

Song, Xiang; Wang, Xinzhao; Liu, Zhaoyun; Yu, Zhiyong

doi:10.3389/fonc.2020.597434

Cited by 108 publications

(65 citation statements)

References 46 publications

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“…Although numerous studies 10 , 11 , 12 , 13 have investigated the genes that might regulate cancer cell death through ferroptosis, their correlations with prognosis remain worth exploring. In this article, we explored the expression levels of 259 ferritinophagy‐related genes in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

The role of ferroptosis‐related genes for overall survival prediction in breast cancer

Jin

Zhu

et al. 2021

Clinical Laboratory Analysis

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Background Ferroptosis is a novel iron‐dependent form of cell death, which is implicated in various diseases including cancers. However, the influence of ferroptosis‐related genes on the prognosis of breast cancer remains unclear. Methods RNA sequencing data of 1053 breast cancer tissue samples and 111 normal tissue samples from The Cancer Genome Atlas (TCGA) were analyzed. Expression levels of 259 ferroptosis‐related genes were compared. Gene Ontology (GO) and the Kyoto Gene and Genomic Encyclopedia (KEGG) analyses were conducted on differentially expressed genes. Cox univariate analysis was conducted to explore the potential prognostic biomarkers of breast cancer. Infiltrating immune cell status was assessed. Results A total of 66 ferroptosis‐related genes were differentially expressed in breast cancer tissues. The enriched GO terms included Biological Process (mainly included response to oxidative stress, cellular response to chemical stress, multicellular organismal homeostasis, cofactor metabolic process, response to metal ion, response to steroid hormone, cellular response to oxidative stress, transition metal ion homeostasis, iron ion homeostasis, and cellular iron ion homeostasis), Cellular Component (mainly included apical plasma membrane, early endosome, apical part of cell, lipid droplet, basolateral plasma membrane, blood microparticle, clathrin‐coated pit, caveola, astrocyte projection, and pronucleus) and Molecular Function (mainly included iron ion binding, ubiquitin protein ligase binding, oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, oxidoreductase activity, acting on the CH−OH group of donors, NAD or NADP as acceptor, ferric iron binding, aldo−keto reductase (NADP) activity, oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, steroid dehydrogenase activity, alditol:NADP+1−oxidoreductase activity, and alcohol dehydrogenase (NADP+) activity). The enriched KEGG pathway mainly included the HIF‐1 signaling pathway, NOD‐like receptor signaling pathway, ferroptosis, IL‐17 signaling pathway, central carbon metabolism in cancer, PPAR signaling pathway, PD‐L1 expression, and PD‐1 checkpoint pathway in cancer. Among them, 38 ferroptosis‐related genes were significantly associated with the prognosis of breast cancer. The prognostic model was constructed, and breast cancer patients in low‐risk group had a better prognosis. In addition, risk score of ferroptosis prognostic model was negatively correlated with B cells (r = −0.063, p = 0.049), CD8+ T cells (r = −0.083, p = 0.010), CD4+ T cells (r = −0.097, p = 0.002), neutrophils (r = −0.068, p = 0.033), and dendritic cells (r = 0.088, p = 0.006). Conclusions The ferroptosis pathway plays a key role in breast cancer. Some differentially expressed ferroptosis‐related genes can be used as prognostic biomarkers for breast cancer.

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Section: Discussionmentioning

confidence: 99%

The role of ferroptosis‐related genes for overall survival prediction in breast cancer

Jin

Zhu

et al. 2021

Clinical Laboratory Analysis

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“…Apatinib promotes ferroptosis in colorectal cancer by targeting ELOVL6/ACSL4 ( Tian et al, 2021 ). Inhibition of GPX4 can induce ferroptosis and enhance the sensitivity of triple-negative breast cancer to gefitinib ( Song et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A New Ferroptosis-Related lncRNA Signature Predicts the Prognosis of Bladder Cancer Patients

Chen

Nie

et al. 2021

Front. Cell Dev. Biol.

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Background: Ferroptosis is closely related to the occurrence and development of cancer. An increasing number of studies have induced ferroptosis as a treatment strategy for cancer. However, the predictive value of ferroptosis-related lncRNAs in bladder cancer (BC) still need to be further elucidated. The purpose of this study was to construct a predictive signature based on ferroptosis-related long noncoding RNAs (lncRNAs) to predict the prognosis of BC patients.Methods: We downloaded RNA-seq data and the corresponding clinical and prognostic data from The Cancer Genome Atlas (TCGA) database and performed univariate and multivariate Cox regression analyses to obtain ferroptosis-related lncRNAs to construct a predictive signature. The Kaplan-Meier method was used to analyze the overall survival (OS) rate of the high-risk and low-risk groups. Gene set enrichment analysis (GSEA) was performed to explore the functional differences between the high- and low-risk groups. Single-sample gene set enrichment analysis (ssGSEA) was used to explore the relationship between the predictive signature and immune status. Finally, the correlation between the predictive signature and the treatment response of BC patients was analyzed.Results: We constructed a signature composed of nine ferroptosis-related lncRNAs (AL031775.1, AL162586.1, AC034236.2, LINC01004, OCIAD1-AS1, AL136084.3, AP003352.1, Z84484.1, AC022150.2). Compared with the low-risk group, the high-risk group had a worse prognosis. The ferroptosis-related lncRNA signature could independently predict the prognosis of patients with BC. Compared with clinicopathological variables, the ferroptosis-related lncRNA signature has a higher diagnostic efficiency, and the area under the receiver operating characteristic curve was 0.707. When patients were stratified according to different clinicopathological variables, the OS of patients in the high-risk group was shorter than that of those in the low-risk group. GSEA showed that tumor- and immune-related pathways were mainly enriched in the high-risk group. ssGSEA showed that the predictive signature was significantly related to the immune status of BC patients. High-risk patients were more sensitive to anti-PD-1/L1 immunotherapy and the conventional chemotherapy drugs sunitinib, paclitaxel, cisplatin, and docetaxel.Conclusion: The predictive signature can independently predict the prognosis of BC patients, provides a basis for the mechanism of ferroptosis-related lncRNAs in BC and provides clinical treatment guidance for patients with BC.

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“…Glutathione peroxidase 4 (GPX4) is the main regulator of ferroptosis, which is pivotal for triple-negative BC cell growth. Song et al [ 17 ] found that GPX4 expression was upregulated in gefitinib-resistant cells and knockdown of GPX4 in vitro and in vivo inhibited cell viability, reduced clonal formation, promoted apoptosis, and increased the cell sensitivity to gefitinib by promoting ferroptosis. Zhang and colleagues [ 23 ] recently reported that suppression of circRHOT1 inhibited cell proliferation, invasion and migration, and promoted apoptosis of BC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Ferroptosis has been recently suggested as a promising target to inhibit tumor growth and trigger cell death, especially in malignant tumors that are resistant to traditional therapies [ 16 ]. Roles and molecular mechanisms of ferroptosis in BC have been investigated in several studies [ 17 , 18 ]. Recent studies have investigated the key mechanisms regulating ferroptosis in BC [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Identification and validation of a ferroptosis-related gene signature predictive of prognosis in breast cancer

2021

Aging

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Ferroptosis, a novel form of regulated cell death, is closely associated with the occurrence and development of malignant tumors. Here, we utilized a bioinformatics approach to identify ferroptosis-related genes to establish a robust and reliable prognostic signature in breast cancer (BC). Univariate Cox regression and LASSO regression analyses of patient’s survival and gene expression data identified a prognostic signature consisting of 10 ferroptosis-related genes (FRGs). The signature demonstrated a favorable prediction performance, and was validated in two independent datasets, GSE21653 and GSE25066. Analyses of immune infiltrates, tumor microenvironment, immune checkpoints, mutations, drug sensitivity, and clinicopathological features revealed significant differences between low- and high-risk BC patients. A multivariate analysis revealed that the signature was an independent prognostic predictor in BC, and a nomogram combining the risk score and tumor stage intuitively displayed high accuracy and reliability with respect to predicting the survival outcomes of BC patients. These findings indicate that the identified prognostic signature is a potential indicator predictive of prognosis and immunotherapeutic responses in BC patients.

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Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

Cited by 108 publications

References 46 publications

The role of ferroptosis‐related genes for overall survival prediction in breast cancer

The role of ferroptosis‐related genes for overall survival prediction in breast cancer

A New Ferroptosis-Related lncRNA Signature Predicts the Prognosis of Bladder Cancer Patients

Identification and validation of a ferroptosis-related gene signature predictive of prognosis in breast cancer

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