High-fat diet aggravates colitis-associated carcinogenesis by evading ferroptosis in the ER stress-mediated pathway

Zhang, Xiaoli; Li, Weiwei; Zhao, Xinhua; He, Longmei; Sun, Ping; Wang, Hongying

doi:10.1016/j.freeradbiomed.2021.10.022

Cited by 41 publications

(28 citation statements)

References 54 publications

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“…Supplementing cells with PUFAs promotes ferroptosis, whereas monounsaturated fatty acids (MUFAs) suppress ferroptosis by inhibiting lipid peroxidation (Tesfay et al, 2019). In line with this, we find that the MUFA oleic acid suppressed ferroptosis (Zhang et al, 2021), partly by displacing PUFAs from plasma membrane phospholipids. In addition, a high fat diet (HFD), which induces systemic accumulation of lipids and their metabolites, could repress ferroptosis in the intestinal epithelial cells (IECs) (Zhang et al, 2022a), indicating the necessity of distinguishing the effect of different lipid components of the diet on ferroptosis.…”

Section: Lipid Peroxidationsupporting

confidence: 74%

“…Iron levels, particularly that of ferrous iron, are significantly elevated in various pathological processes involving ferroptosis, such as hemorrhagic brain and ulcerative colitis (Li et al, 2017;Xu et al, 2020). Our previous study shows that ferroptosis is involved in intestinal epithelial cell death during colitis-associated carcinogenesis and is accompanied by elevated ferrous iron level in colon tissues (Zhang et al, 2021). Moreover, the classical ferroptosis inducers erastin or 1S, 3R-RSL3 (RSL3) can increase intracellular iron (Dixon et al, 2012).…”

Section: Iron Overloadmentioning

confidence: 99%

“…Due to the inability of PTGS2 to directly oxidize lipids, it is usually considered as a biomarker, but not as a driver, of ferroptosis (Tang et al, 2021). In addition, RSL3 can elevate the AKR1C1, CHAC1, FTH1, and PTGS2 expression in various cell lines (Zhang et al, 2021).…”

Section: Genetics Featuresmentioning

confidence: 99%

“…Augmented oxidative stress in chronic inflammation causes oxidative damage to macromolecules, contributes to genomic instability, affects cell viability, and promotes carcinogenesis (Sung et al, 2021;Zhang et al, 2021). Our research reveals that ferroptosis is involved in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced tumors in mice, as evidenced by elevated iron levels, lipid peroxidation, and ferroptotic markers, as well as shrunken mitochondria with disrupted cristae (Zhang et al, 2021). Crucially, the ferroptosis-specific inhibitor Fer-1 aggravates colonic tumors (Figure 4) (Zhang et al, 2021).…”

Section: Ferroptosis and Colorectal Cancermentioning

confidence: 99%

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Ferroptosis as a therapeutic target for inflammation-related intestinal diseases

Zhang

Lv²,

Wang³

2023

Front. Pharmacol.

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Ferroptosis is an iron-dependent programmed cell death characterized by reactive oxygen species-induced lipid peroxidation and resultant membrane damage. Recent research has elucidated the mechanism of ferroptosis and investigated the relationship between ferroptosis and various diseases, including degenerative diseases, cancer, and inflammation. Ferroptosis is associated with inflammation-related intestinal diseases such as colitis and colitis-associated cancer. New insights into the role of ferroptosis in the pathogenesis of inflammation-related gut diseases have suggested novel therapeutic targets. In this review, we summarize current information on the molecular mechanisms of ferroptosis and describe its emerging role and therapeutic potential in inflammation-related intestinal diseases.

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Section: Lipid Peroxidationsupporting

confidence: 74%

Section: Iron Overloadmentioning

confidence: 99%

Section: Genetics Featuresmentioning

confidence: 99%

Section: Ferroptosis and Colorectal Cancermentioning

confidence: 99%

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Ferroptosis as a therapeutic target for inflammation-related intestinal diseases

Zhang

Lv²,

Wang³

2023

Front. Pharmacol.

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“…RSL3 is a valuable tool compound for cell culture settings. Although several studies have demonstrated the efficacy of RSL3 in various animal models (20,31,32), non-specific effects of RSL3 cannot be excluded given its poor bioavailability in vivo (16). Given the therapeutic promise of ferroptosis induction in persister cells, the development of a potent bioavailable GPX4 inhibitor suitable for use with CRC xenografts is an urgent priority.…”

Section: Discussionmentioning

confidence: 99%

Glutathione Peroxidase 4 as a Therapeutic Target for Anti-Colorectal Cancer Drug-Tolerant Persister Cells

Zhang

Ma²,

Yang³

et al. 2022

Front. Oncol.

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BackgroundDespite the effectiveness of chemotherapy and targeted therapy for colorectal cancer, drug resistance drives therapy failure and tumor relapse. Increasing evidence has suggested that cancer cells can enter a reversible drug-tolerant persister state to survive chemotherapy or targeted agents. However, the traits and treatable vulnerabilities of anti-colorectal cancer drug-tolerant persister cells is not yet known.MethodsIn this study, we established 5-fluorouracil and AZ628-tolerant persister cell models in two colorectal cancer cell lines, namely HCT116 and SW620, and revealed the characteristics of colorectal cancer persister cells by cell viability assay and flow cytometry. We investigated the efficacy and mechanism of ferroptosis inducers RSL3 and FIN56 on persister cells, which are glutathione peroxidase 4 inhibitors. In the xenograft mouse model, we further evaluated the inhibitory effect of RSL3 on tumor regrowth.ResultsColorectal cancer persister cells, which were enriched in the residual cancer cell population, exhibited reduced drug sensitivity, were largely quiescent and expressed high levels of stem cell-related genes and mesenchymal markers but not epithelial markers. The persister cells were more sensitive and underwent ferroptosis induced by glutathione peroxidase 4 inhibitors. Mechanistically, glutathione peroxidase 4 and ferrous iron, which are pivotal ferroptosis regulators, were upregulated in residual cells or tumors, and were hence potential therapeutic targets of persister cells. In the xenograft model, we confirmed that inhibition of glutathione peroxidase 4 restrained tumor regrowth after discontinuation of anti-cancer drug treatment. Moreover, biopsies obtained from patients with colorectal cancer undergoing neoadjuvant chemoradiotherapy revealed upregulated glutathione peroxidase 4 and ferritin heavy chain 1. High glutathione peroxidase 4 expression correlates with a worse prognosis in colorectal cancer patients.ConclusionsOur work reveals that the upregulated glutathione peroxidase 4 and ferrous iron in anti-colorectal cancer drug-tolerant persister cells were potential therapeutic targets. Glutathione peroxidase 4 inhibition combined with chemotherapy or targeted therapy may be a promising therapy for colorectal cancer.

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SELENOI Functions as a Key Modulator of Ferroptosis Pathway in Colitis and Colorectal Cancer

Huang,

Yang,

Zhang

et al. 2024

Advanced Science

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Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether‐linked phosphatidylethanolamine (ePE) and a marked increase in ether‐linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate‐15‐lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI‐knockdown cells, while SELENOI overexpression can partially rescue GPX4‐knockdown‐induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.

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High-fat diet aggravates colitis-associated carcinogenesis by evading ferroptosis in the ER stress-mediated pathway

Cited by 41 publications

References 54 publications

Ferroptosis as a therapeutic target for inflammation-related intestinal diseases

Ferroptosis as a therapeutic target for inflammation-related intestinal diseases

Glutathione Peroxidase 4 as a Therapeutic Target for Anti-Colorectal Cancer Drug-Tolerant Persister Cells

SELENOI Functions as a Key Modulator of Ferroptosis Pathway in Colitis and Colorectal Cancer

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