Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance

Elgendy, Sara M.; Alyammahi, Shatha K.; Alhamad, Dima W.; Abdin, Shifaa M.; Omar, Hany A.

doi:10.1016/j.critrevonc.2020.103095

Cited by 93 publications

(74 citation statements)

References 181 publications

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“…So can we explore whether these lncRNAs regulate these variables and how to regulate them? There have been many studies about ferroptosis in the drug resistance of tumor patients [49,50]. The current study demonstrated the prognostic signi cance of these ferroptosis-related lncRNAs and signature in CRC.…”

Section: Based On the Strati Cation Of Clinical Variables The Correlsupporting

confidence: 62%

A Novel Ferroptosis-related Lncrna Prognostic Signature for Colorectal Cancer by Bioinformatics Analysis

Yang

Zhang

Wang

et al. 2021

Preprint

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Background: Recently, extensive studies have shown that ferroptosis in cancer treatment has been increasingly confirmed. The current study aims to construct a robust ferroptosis-related lncRNAs signature prediction model of colorectal cancer (CRC) patients by bioinformatics analysisMethods: The transcriptome data were abstracted from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs were screened by comparing 568 CRC tissues with 44 adjacent non-CRC tissues. Univariate Cox regression, lasso regression, multivariate Cox regression were conducted to design a ferroptosis-related lncRNA signature. This signature’s prognosis was verified by the log-rank test of Kaplan-Meier curve and the area under curve (AUC) of receiver operating characteristic (ROC) in train set, test set, and entire set. Furthermore, univariate and multivariate Cox regression were used to analyze its independent prognostic ability. The relationship of the ferroptosis-linked lncRNAs' expression and clinical variables was demonstrated by Wilcoxon rank-sum test and Kruskal-Wallis test. Gene set enrichment analysis (GSEA) was performed to signaling pathways it may involve.Results: 2541 differentially expressed lncRNAs were screened, of which 439 are ferroptosis-related lncRNAs. A seven ferroptosis-related lncRNAs (AC005550.2, LINC02381, AL137782.1, C2orf27A, AC156455.1, AL354993.2, AC008760.1) prognostic signature was constructed, validated and evaluated. This model's prognosis in the high-risk group is obviously worse than that of the low-risk group in train set, test set, and entire set. The AUC of ROC predicting the three years survival in the train set, test set, and entire set was 0.796, 0.715, and 0.758, respectively. Moreover, the designed molecular signature was found to be an independent prognostic variable. Compared to clinical variables, this signature's ROC curves demonstrated the second largest AUC value (0.737). The expression of these lncRNAs and the lncRNA signature are related to distant metastasis, Lymph-node status, clinical stage, T stage, KRAS mutation, BRAF mutation, MMR status, and perineural invasion. Finally, GSEA analysis results show that the signature is involved in six metabolism-related pathways.Conclusion: The current study constructed, validated, and evaluated a seven ferroptosis-related lncRNA signature which can independently be used to predict the prognosis of CRC patients, and it may become a new therapeutic target.

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Section: Based On the Strati Cation Of Clinical Variables The Correlsupporting

confidence: 62%

A Novel Ferroptosis-related Lncrna Prognostic Signature for Colorectal Cancer by Bioinformatics Analysis

Yang

Zhang

Wang

et al. 2021

Preprint

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“…We evaluated 60 ferroptosis-related genes ( Chen et al, 2020 ; Elgendy et al, 2020 ). “Limma” was used to identify differentially expressed genes (DEGs) in two groups, normal samples and tumor samples, with a false discovery rate <0.05.…”

Section: Methodsmentioning

confidence: 99%

Ferroptosis-Related Gene-Based Prognostic Model and Immune Infiltration in Clear Cell Renal Cell Carcinoma

Zhao

et al. 2021

Front. Genet.

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Clear cell renal cell carcinoma (ccRCC) is one of the most common tumors in the urinary system. Ferroptosis plays a vital role in ccRCC development and progression. We did an update of ferroptosis-related multigene expression signature for individualized prognosis prediction in patients with ccRCC. Differentially expressed ferroptosis-related genes in ccRCC and normal samples were screened using The Cancer Genome Atlas. Univariate and multivariate Cox regression analyses and machine learning methods were employed to identify optimal prognosis-related genes. CARS1, CD44, FANCD2, HMGCR, NCOA4, SLC7A11, and ACACA were selected to establish a prognostic risk score model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these genes were mainly enriched in immune-related pathways; single-sample Gene Set Enrichment Analysis revealed several immune cells potentially related to ferroptosis. Kaplan–Meier survival analysis demonstrated that patients with high-risk scores had significantly poor overall survival (log-rank P = 7.815 × 10–11). The ferroptosis signature was identified as an independent prognostic factor. Finally, a prognostic nomogram, including the ferroptosis signature, age, histological grade, and stage status, was constructed. Analysis of The Cancer Genome Atlas-based calibration plots, C-index, and decision curve indicated the excellent predictive performance of the nomogram. The ferroptosis-related seven-gene risk score model is useful as a prognostic biomarker and suggests therapeutic targets for ccRCC. The prognostic nomogram may assist in individualized survival prediction and improve treatment strategies.

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“…Whether as monotherapy or in combination with other chemotherapeutic drugs, ferroptosis inducers can induce ferroptosis in cancer cells, especially in drug-resistant cancer cells 9 . In addition, ferroptosis can selectively target aggressive cancer stem cells and is also expected to enhance the efficacy of immunotherapy and overcome the resistance to immunotherapy 10 , 11 . Erastin is a ferroptosis inducer that functionally inhibits cystine-glutamate reverse transporter (System Xc-).…”

Section: Introductionmentioning

confidence: 99%

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Wei¹,

Zhao²,

Wang³

et al. 2021

Int. J. Biol. Sci.

242

102

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Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron-and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion:In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.

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Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance

Cited by 93 publications

References 181 publications

A Novel Ferroptosis-related Lncrna Prognostic Signature for Colorectal Cancer by Bioinformatics Analysis

A Novel Ferroptosis-related Lncrna Prognostic Signature for Colorectal Cancer by Bioinformatics Analysis

Ferroptosis-Related Gene-Based Prognostic Model and Immune Infiltration in Clear Cell Renal Cell Carcinoma

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

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