Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation

Goji, Takeo; Takahara, Kazuhiko; Negishi, Manabu; Katoh, Hironori

doi:10.1074/jbc.m117.814392

Cited by 94 publications

(110 citation statements)

References 43 publications

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“…5D). These findings corroborate recent reports that system xcactivity and expression is required for glucose deprivation-induced cell death 14,16,24 .…”

Section: L-cystine Drives Glucose Deprivation-induced Cell Deathsupporting

confidence: 92%

“…Among the GBM cell lines, we found that A172 exhibited strong resistance, LN229 and U118MG exhibited medium sensitivity, and LN18, T98, and U87 exhibited high sensitivity to glucose deprivation ( Fig. 1A) 23,24 . For the sarcoma cell lines, HT161 and TC32 exhibited resistance and sensitivity, respectfully, to glucose deprivation (Supporting Fig.…”

Section: Metabolomics Identifies Accumulation Of L-cystine and L-cystmentioning

confidence: 96%

“…In sensitive cells, it has been shown that glucose deprivation induces high levels of reactive oxygen species (ROS), and that elevated ROS levels are responsible for glucose deprivation-induced cell death 9,23,24 . We thus measured ROS levels at multiple time points following glucose deprivation.…”

Section: Nadph Is the Limiting Reducing Agent In Glucose-deprived Canmentioning

confidence: 99%

“…System xccomprises a heterodimer containing a non-specific heavy chain, SLC3A2, and a specific light chain, xCT/SLC7A11. Recent reports have shown that system xcactivity promotes cancer cell dependency on glucose 14,16,24 , although the mechanism by which system xcpromotes glucose deprivation-induced cell death remains disputed. Therefore, we sought to test the role of system xcin L-cystine accumulation and cell death observed following glucose deprivation.…”

Section: L-cystine Drives Glucose Deprivation-induced Cell Deathmentioning

confidence: 99%

“…This glucose or glutamine "addiction" has been linked to signaling through AKT and AMPK [8][9][10] , mTORC1 11 , and tyrosine kinases 12 . Other studies have linked glucose deprivationinduced death to mechanisms independent of glycolysis including Ca 2+ influxes through the L-type calcium channel Cav1.3 13 and the glutamate/cystine antiporter xCT (SLC7A11) [14][15][16] . However, therapeutically targeting the glucose addiction phenotype remains a challenge 2 because 1) tumors cannot be completely starved of glucose in vivo;…”

Section: Introductionmentioning

confidence: 99%

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NADPH consumption by L-cystine reduction creates a metabolic vulnerability upon glucose deprivation

Joly¹,

Delfarah²,

Phung³

et al. 2019

Preprint

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The consequences of metabolic reprogramming in cancer can include an increased dependence on metabolic substrates such as glucose for survival. As such, the vulnerability of cancer cells to glucose deprivation creates an attractive opportunity for therapeutic intervention. Because it is not possible to starve tumors of glucose in vivo, we sought to identify the mechanisms regulating cancer cell death upon glucose deprivation and then design combinations of inhibitors to mimic glucose deprivation-induced cell death. Using metabolomic profiling, we found that cells undergoing glucose deprivationinduced cell death exhibited dramatic accumulation of intracellular L-cysteine and its oxidized dimer, L-cystine, and depletion of the antioxidant glutathione. Building on this observation, we show that glucose deprivation-induced cell death is driven not by lack of glucose but rather by L-cystine import. Following glucose deprivation, the import of Lcystine and subsequent reduction to L-cysteine depleted both NADPH and glutathione, thereby allowing toxic accumulation of reactive oxygen species. Consistent with this model, we found that the glutamate/cystine antiporter, xCT, was required for sensitivity to glucose deprivation. We searched for glycolytic enzymes whose expression is essential for survival of cancer cells with high xCT expression and identified the glucose transporter GLUT1. We therefore tested a drug combination co-targeting GLUT1 and glutathione synthesis and found that these drugs induced synthetic lethal cell death in high xCTexpressing cell lines susceptible to glucose deprivation. These results indicate that cotargeting GLUT1 and glutathione synthesis is a potential therapeutic approach in tumors dependent on glucose for survival. L-cystine drives glucose deprivation-induced cell deathIntroduction:

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“…5D). These findings corroborate recent reports that system xcactivity and expression is required for glucose deprivation-induced cell death 14,16,24 .…”

Section: L-cystine Drives Glucose Deprivation-induced Cell Deathsupporting

confidence: 92%

Section: Metabolomics Identifies Accumulation Of L-cystine and L-cystmentioning

confidence: 96%

Section: Nadph Is the Limiting Reducing Agent In Glucose-deprived Canmentioning

confidence: 99%

Section: L-cystine Drives Glucose Deprivation-induced Cell Deathmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

NADPH consumption by L-cystine reduction creates a metabolic vulnerability upon glucose deprivation

Joly¹,

Delfarah²,

Phung³

et al. 2019

Preprint

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A Ferroptosis‐Inhibitive Polypeptosome for Synergistic Management of Acute Kidney Injury Through Antioxidation and Iron Binding

Liu,

Zhang,

Fan

et al. 2024

Adv Funct Materials

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Acute kidney injury (AKI) is a critical condition with a wide range of triggers that cause heavy burden on public health. Despite its high incidence and mortality, the treatment of AKI still highly relies on hemodialysis, which is costly and usually accompanied by severe complications. Therefore, development of new therapeutic targets and methods for AKI is urgently needed. Herein, a ferroptosis‐targeting strategy for AKI treatment by rationally designed ferroptosis‐inhibitive polypeptide‐based polymersomes (polypeptosomes, FIPs) is proposed. Such FIPs are self‐assembled from poly(glutamic acid)‐block‐poly(methionine‐stat‐tyrosine) [PGA9‐b‐P(Met8‐stat‐PTyr13)]. The ferroptosis‐inhibition function of the FIPs arises from the rationally‐selected amino acid composition: P(Met‐stat‐Tyr) endows the FIPs with a high scavenging efficiency of over 90% toward different reactive oxygen species (ROS); while the glutamate and tyrosine residues, as well as the amide groups, can bind iron ions, thus blocking iron overload and lipid peroxide in cells. In vivo experiments confirm that the FIPs can effectively alleviate oxidative stress, inhibit ferroptosis, and restore kidney functions. Transcriptome sequencing further reveals the therapeutic mechanisms of FIPs. Overall, such polypeptosomes capable of blocking multiple pathways of ferroptosis open a new avenue for AKI treatment and provide fresh insights into the development of generalized therapies for inflammation.

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Amino acid abundance and composition in cell culture medium affects trace metal tolerance and cholesterol synthesis

Rawat

Bhambri

Pandey

et al. 2022

Biotechnology Progress

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Amino acid compositions of cell culture media are empirically designed to enhance cell growth and productivity and vary both across media formulations and over the course of culture due to imbalance in supply and consumption. The interconnected nature of the amino acid transporters and metabolism suggests that changes in amino acid composition can affect cell physiology. In this study, we explore the effect of a step change in amino acid composition from a DMEM: F12-based medium to a formulation varying in relative abundances of all amino acids, evaluated at two amino acid concentrations (lean LAA vs. rich HAA). Cell growth was inhibited in LAA but not HAA. In addition to the expected effects on expression of the cell cycle, amino acid response and mTOR pathway genes in LAA, we observed an unanticipated effect on zinc uptake and efflux genes. This was accompanied by a lower tolerance to zinc supplementation in LAA but not in the other formulations. Histidine was sufficient but not necessary to prevent such zinc toxicity. Additionally, an unanticipated downregulation of genes in the cholesterol synthesis pathway was observed in HAA, accompanied by an increase in cellular cholesterol content, which may depend on the relative abundances of glutamine and other amino acids. This study shows that changes in the amino acid composition without any evident effect on growth may have profound effects on metabolism. Such analyses can help rationalize the designing of medium and feed formulations for bioprocess applications beyond replenishment of consumed components.

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Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation

Cited by 94 publications

References 43 publications

NADPH consumption by L-cystine reduction creates a metabolic vulnerability upon glucose deprivation

NADPH consumption by L-cystine reduction creates a metabolic vulnerability upon glucose deprivation

A Ferroptosis‐Inhibitive Polypeptosome for Synergistic Management of Acute Kidney Injury Through Antioxidation and Iron Binding

Amino acid abundance and composition in cell culture medium affects trace metal tolerance and cholesterol synthesis

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