A synthetic lethal drug combination mimics glucose deprivation–induced cancer cell death in the presence of glucose

Joly, James H.; Delfarah, Alireza; Phung, Philip S.; Parrish, Sydney; Graham, Nicholas A.

doi:10.1016/s0021-9258(17)49891-7

Cited by 63 publications

(28 citation statements)

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“…Recent evidence also indicated that, as a transmembrane protein localized on the plasma membrane, SLC7A11 is also subjected to regulation by lysosomal degradation. As detailed in a later section, SLC7A11 promotes glucose dependency, leading to the exquisite vulnerability of cancer cells with high SLC7A11 expression (SLC7A11 high ) to glucose starvation (Goji et al, 2017;Koppula et al, 2017;Shin et al, 2017;Joly et al, 2020;Liu et al, 2020). It is known that cells cultured at high density survive much better than those cultured at low density under glucose starvation.…”

Section: Posttranslational Regulation Of Slc7a11mentioning

confidence: 99%

“…However, a recent study showed that SLC7A11 overexpression does not promote glycolytic flux and that 2-deoxyglucose (2DG), a glycolysis inhibitor, even rescues glucose starvation-induced cell death in SLC7A11 high cancer cells (the underlying mechanism will be described below) (Koppula et al, 2017;Shin et al, 2017). Furthermore, it was shown that cystine starvation rescues the cell death in SLC7A11 high cancer cells under glucose starvation, suggesting that it is cystine import that underlies glucose starvation-induced cell death in SLC7A11 high cancer cells (Goji et al, 2017;Joly et al, 2020;Liu et al, 2020).…”

Section: Slc7a11-induced Glucose Dependency In Cancer Cellsmentioning

confidence: 99%

“…Correspondingly, considerable interest has been directed toward understanding the role and regulatory mechanisms of SLC7A11 in ferroptosis and tumor biology as well as therapeutically targeting SLC7A11 in cancer therapy. Another fascinating topic in SLC7A11 research in recent years has been to uncover the role of SLC7A11 in inducing nutrient dependency in cancer cells (Goji et al, 2017;Koppula et al, 2017;Muir et al, 2017;Romero et al, 2017;Sayin et al, 2017;Shin et al, 2017;Koppula et al, 2018;Joly et al, 2020;Liu et al, 2020). (Here nutrient dependency refers to the phenomenon wherein metabolic reprogramming renders cancer cells to be highly dependent on certain nutrients for survival and growth, such that removal of such nutrients will selectively kill or halt the growth of cancer cells that are dependent on these nutrients while having less harmful effects on other cancer cells or normal cells.)…”

Section: Introductionmentioning

confidence: 99%

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Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

2020

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The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and glutamine-dependency in SLC7A11high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and -independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.

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Section: Posttranslational Regulation Of Slc7a11mentioning

confidence: 99%

Section: Slc7a11-induced Glucose Dependency In Cancer Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

2020

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“…Reduction of intracellular cystine consumes NADPH (Pader et al, 2014). When NADPH is limited due to starvation (Goji et al, 2017;Joly et al, 2020;Liu et al, 2020), cystine switches from being a precursor of the GSH antioxidant into an oxidative toxin by further depleting NADPH. Moreover, cystine uptake is coupled in a 1:1 ratio to glutamate export through the cystine-glutamate antiporter system xCT (or Xc − ) that is encoded by the SLC7A11 gene (Bannai, 1986;Koppula et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…These include nutrient transport and its links to intracellular glutathione metabolism (Reed et al, 2008;Geenen et al, 2012Geenen et al, , 2013, ROS-mediated signaling at the plasma membrane and across mitochondrial networks (Zhou et al, 2010;Grecco et al, 2011;Nivala et al, 2011;Travasso et al, 2017), as well as the ferroptosis signaling cascade (Konstorum et al, 2020). However, none of these models integrate nutrient metabolism and ROS-mediated signaling as a redox system, nor did the respective studies investigate how deprivation of redox-modulating nutrientsglucose, cystine, and glutamine, particularly via the cystineglutamate antiporter SLC7A11 (Goji et al, 2017;Joly et al, 2020;Liu et al, 2020)-may lead to elevated ROS and, consequently, cell death.…”

Section: Introductionmentioning

confidence: 99%

Multistability maintains redox homeostasis in human cells

Huang

Lee

et al. 2021

Molecular Systems Biology

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Cells metabolize nutrients through a complex metabolic and signaling network that governs redox homeostasis. At the core of this, redox regulatory network is a mutually inhibitory relationship between reduced glutathione and reactive oxygen species (ROS)—two opposing metabolites that are linked to upstream nutrient metabolic pathways (glucose, cysteine, and glutamine) and downstream feedback loops of signaling pathways (calcium and NADPH oxidase). We developed a nutrient‐redox model of human cells to understand system‐level properties of this network. Combining in silico modeling and ROS measurements in individual cells, we show that ROS dynamics follow a switch‐like, all‐or‐none response upon glucose deprivation at a threshold that is approximately two orders of magnitude lower than its physiological concentration. We also confirm that this ROS switch can be irreversible and exhibits hysteresis, a hallmark of bistability. Our findings evidence that bistability modulates redox homeostasis in human cells and provide a general framework for quantitative investigations of redox regulation in humans.

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Machine learning identification and immune infiltration of disulfidptosis‐related Alzheimer's disease molecular subtypes

Zhu,

Kong,

Han

et al. 2023

Immunity Inflam & Disease

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BackgroundAlzheimer's disease (AD) is a common neurodegenerative disorder. Disulfidptosis is a newly discovered form of programmed cell death that holds promise as a therapeutic strategy for various disorders. However, the functional roles of disulfidptosis‐related genes (DRGs) in AD remain unknown.MethodsMicroarray data and clinical information from patients with AD and healthy controls were downloaded from the Gene Expression Omnibus database. A thorough examination of DRG expression and immune characteristics in both groups was performed. Based on the identified DRGs, we performed an unsupervised clustering analysis to categorize the AD samples into various disulfidptosis‐related molecular clusters. Weighted gene co‐expression network analysis was performed to select hub genes specific to disulfidptosis‐related AD clusters. The performances of various machine learning models were compared to determine the optimal predictive model. The predictive ability of the optimal model was assessed using nomogram analysis and five external datasets.ResultsEight DRGs showed differential expression between the AD and control samples. Two different molecular clusters were identified. The immune cell infiltration analysis revealed distinct differences in the immune microenvironment of the two clusters. The support vector machine model showed the highest performance, and a panel of five signature genes was identified, which showed excellent performance on the external validation datasets. The nomogram analysis also showed high accuracy in predicting AD.ConclusionWe identified disulfidptosis‐related molecular clusters in AD and established a novel risk model to assess the likelihood of developing AD. These findings revealed a complex association between disulfidptosis and AD, which may aid in identifying potential therapeutic targets for this debilitating disorder.

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A synthetic lethal drug combination mimics glucose deprivation–induced cancer cell death in the presence of glucose

Cited by 63 publications

References 63 publications

Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

Multistability maintains redox homeostasis in human cells

Machine learning identification and immune infiltration of disulfidptosis‐related Alzheimer's disease molecular subtypes

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