System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

Li, Feng‐Jiao; Long, Hui-Zhi; Zhou, Ziwei; Luo, Hongyu; Xu, Shuo-Guo; Gao, Lichen

doi:10.3389/fphar.2022.910292

Cited by 121 publications

(77 citation statements)

References 285 publications

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“…GSH depletion is responsible for iron-catalyzed, lipid peroxidation-dependent, non-apoptotic cell death, known as ferroptosis [ 5 , 6 , 7 ]. The induction of ferroptosis by GSH depletion has been shown to selectively kill resilient cancer cells resistant to conventional treatments in various types of human cancers [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

Lee

Roh

2022

Antioxidants

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SLC7A11 is a cell transmembrane protein composing the light chain of system xc−, transporting extracellular cystine into cells for cysteine production and GSH biosynthesis. SLC7A11 is a critical gateway for redox homeostasis by maintaining the cellular levels of GSH that counter cellular oxidative stress and suppress ferroptosis. SLC7A11 is overexpressed in various human cancers and regulates tumor development, proliferation, metastasis, microenvironment, and treatment resistance. Upregulation of SLC7A11 in cancers is needed to adapt to high oxidative stress microenvironments and maintain cellular redox homeostasis. High basal ROS levels and SLC7A11 dependences in cancer cells render them vulnerable to further oxidative stress. Therefore, cyst(e)ine depletion may be an effective new strategy for cancer treatment. However, the effectiveness of the SLC7A11 inhibitors or cyst(e)inase has been established in many preclinical studies but has not reached the stage of clinical trials for cancer patients. A better understanding of cysteine and SLC7A11 functions regulating and interacting with redox-active proteins and their substrates could be a promising strategy for cancer treatment. Therefore, this review intends to understand the role of cysteine in antioxidant and redox signaling, the regulators of cysteine bioavailability in cancer, the role of SLC7A11 linking cysteine redox signaling in cancer metabolism and targeting SLC7A11 for novel cancer therapeutics.

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Section: Introductionmentioning

confidence: 99%

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

Lee

Roh

2022

Antioxidants

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“…Glutathione is a critical intracellular antioxidant whose function is to detoxify the cell environment of oxPLs and other ROS (15). SLC7A11 is an important part of the system Xc-whose function is cystine uptake resulting in GSH synthesis (16,(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

“…System Xc - containing the SLC7A11/GSH/PLOOH axis act as cystine/glutamate antiport involved in the synthesis of GSH which is converted to oxidized glutathione (GSSG) upon catalytic action of GPX4(15). Compounds such as erastin induce ferroptosis by interfering with cystine uptake by inhibiting the System Xc - (16–19).…”

Section: Introductionmentioning

confidence: 99%

“…The ferroptosis-induced antioxidant activity depends on three (3) systems which are as follows: dihydro-orotate dehydrogenase (DHODH)/ubiquinol; ferroptosis suppressor protein 1 (FSP1)/NAD(P)H/ubiquinol; and SLC7A11/glutathione (GSH)/phospholipid hyperoxide (PLOOH) (14). System Xccontaining the SLC7A11/GSH/PLOOH axis act as cystine/glutamate antiport involved in the synthesis of GSH which is converted to oxidized glutathione (GSSG) upon catalytic action of GPX4 (15). Compounds such as erastin induce ferroptosis by interfering with cystine uptake by inhibiting the System Xc - (16)(17)(18)(19) .…”

Section: Introductionmentioning

confidence: 99%

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NAT10, an RNA acetyl cytidine transferase restrains ferroptosis in cancer cells by maintaining SLC7A11 RNA stability

Dalhat

Choudhry

Khan

2022

Preprint

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Recently, we reported that N-acetyltransferase 10 (NAT10) regulates fatty acid metabolism through ac4C-dependent RNA modification of key genes in cancer cells. During this work, we noticed ferroptosis as one of the most negatively enriched pathways among other pathways in NAT10 depleted cancer cells. In the current work, we explored the possibility of whether NAT10 acts as an epitrancriptomic regulator of ferroptosis pathway in cancer cells. Global ac4C levels and expression of NAT10 with other ferroptosis-related genes were assessed via dotblot and RT-qPCR respectively. Flow cytometry and biochemical analysis were used to assess oxidative stress and ferroptosis features. The ac4C mediated mRNA stability was conducted RIP-PCR and mRNA stability assay. Metabolites were profiled using LC-MS/MS. Our results showed significant downregulation in expression of essential genes related to ferroptosis namely SLC7A11, GCLC, MAP1LC3A, and SLC39A8 in NAT10 depleted cancer cells. Further, we noticed a reduction in cystine uptake and reduced GSH levels along with elevated ROS, and lipid peroxidation levels in NAT10 depleted cells. Consistently, overproduction of oxPLs as well as increased mitochondrial depolarization and decreased activities of antioxidant enzymes support the notion of ferroptosis induction in NAT10 depleted cancer cells. Mechanistically, reduced ac4C level shortens the half-life of GCLC and SLC7A11 mRNA, resulting in low levels of intracellular cystine and reduced GSH, failing to detoxify ROS leading to increased cellular oxPLs which facilitates ferroptosis induction. Collectively, our findings suggest that NAT10 restrains ferroptosis by stabilizing the SLC7A11 mRNA transcripts to avoid oxidative stress that induces oxidation of phospholipids to initiate ferroptosis.

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“…The antioxidant GSH is synthetized from glutamate, cysteine, and glycine with the help of two enzymes, glutamate cysteine ligase (GCL) and glutathione synthetase (GSS), in two steps. Structured as a simple tripeptide, GSH reduces oxidized intracellular components with its reduced thiol group on the cysteine [ 112 ]. The active site of GPx4 shifts between the oxidized and the reduced state in order to maintain its catalytic function.…”

Section: Ferroptosis: Iron- and Lipid-peroxidation-dependent Cell Deathmentioning

confidence: 99%

Iron Brain Menace: The Involvement of Ferroptosis in Parkinson Disease

Lin

Chen

Lin

et al. 2022

Cells

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Parkinson disease (PD) is the second-most common neurodegenerative disease. The characteristic pathology of progressive dopaminergic neuronal loss in people with PD is associated with iron accumulation and is suggested to be driven in part by the novel cell death pathway, ferroptosis. A unique modality of cell death, ferroptosis is mediated by iron-dependent phospholipid peroxidation. The mechanisms of ferroptosis inhibitors enhance antioxidative capacity to counter the oxidative stress from lipid peroxidation, such as through the system xc−/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis and the coenzyme Q10 (CoQ10)/FSP1 pathway. Another means to reduce ferroptosis is with iron chelators. To date, there is no disease-modifying therapy to cure or slow PD progression, and a recent topic of research seeks to intervene with the development of PD via regulation of ferroptosis. In this review, we provide a discussion of different cell death pathways, the molecular mechanisms of ferroptosis, the role of ferroptosis in blood–brain barrier damage, updates on PD studies in ferroptosis, and the latest progress of pharmacological agents targeting ferroptosis for the intervention of PD in clinical trials.

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System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

Cited by 121 publications

References 285 publications

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

NAT10, an RNA acetyl cytidine transferase restrains ferroptosis in cancer cells by maintaining SLC7A11 RNA stability

Iron Brain Menace: The Involvement of Ferroptosis in Parkinson Disease

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