SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells

Yan, Yizhong; Teng, Hongqi; Hang, Qinglei; Kondiparthi, Lavanya; Lei, Guang; Horbath, Amber; Liu, Xiaoguang; Mao, Chao; Wu, Shiqi; Li, Zhuang; You, M. James; Poyurovsky, Masha V.; Ma, Li; Olszewski, Kellen L.; Gan, Boyi

doi:10.1038/s41467-023-39401-9

Cited by 103 publications

(32 citation statements)

References 53 publications

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“…63,64 The expression of the cystine/glutamate antiporter, xCT, also enhances dependency on glucose as increased glutamate is secreted rather than used in downstream metabolic pathways. 65 Further, high expression levels of xCT increases sensitivity to oxidative stress and alters glutamine metabolism, 66,67 consistent with our observation that PKM2KO cells have decreased xCT expression under cystine starvation.…”

Section: Discussionsupporting

confidence: 85%

Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells

Ensink,

Jordan,

D Medeiros

et al. 2023

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporter in vitro. Proof-of-concept in vivo experiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC.

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Section: Discussionsupporting

confidence: 85%

Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells

Ensink,

Jordan,

D Medeiros

et al. 2023

Preprint

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“…Oxidative stress occurs due to the accumulation of reactive oxygen species and is a prominent driver of progressive loss of tissue function during ageing (Liguori et al, 2018). We observed increased transcript levels for the oxidative stress response genes pdk4 (log2FC = 1.16, p-value = 4.98E-12, FDR = 1.81E-10) and slc7a11 (log2FC = 1.48, p-value = 6.25E-15, FDR = 3.62E-13) in the aged killifish retina (Figure 2A) (Gao et al, 2022; Yan et al, 2023). Furthermore, we detected increased transcript levels for the genes tgfb3 (log2FC = 1.04, p-value = 1.54E-11, FDR = 5.10E-10) and rlbp1a (log2FC = 1.03, p-value = 3.31E-15, FDR = 2.05E-13), known to be related to gliosis ( tgfb3 ) (Conedera et al, 2021) and Müller glia homeostasis ( rlbp1a ) (Vázquez-Chona et al, 2009) (Figure 2A).…”

Section: Resultsmentioning

confidence: 94%

“…(log2FC = 1.48, p-value = 6.25E-15, FDR = 3.62E-13) in the aged killifish retina (Figure 2A) (Gao et al, 2022;Yan et al, 2023). Furthermore, we detected increased transcript levels for the genes tgfb3 (log2FC = 1.04, p-value = 1.54E-11, FDR = 5.10E-10) and rlbp1a (log2FC = 1.03, p-value = 3.31E-15, FDR = 2.05E-13), known to be related to gliosis (tgfb3) (Conedera et al, 2021) and Müller glia homeostasis (rlbp1a) (Vázquez-Chona et al, 2009) (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Bergmans,

Noel,

Masin

et al. 2024

Preprint

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Age-related vision loss caused by neurodegenerative pathologies in the retina is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.HighlightsThe aged killifish retina displays several ageing hallmarks, such as oxidative stress, gliosis, and inflammageing, at the transcriptome level.Risk genes for neurodegenerative disorders show dysregulation in the old killifish retina.All vertebrate retinal cell types are present in the killifish retina.Transcriptional dysregulation in the aged killifish retina is observed across cell types.Cell type-specific transcriptomic changes across age highlight increased stress response.

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“…However, cells overexpressing SLC7A11 require a substantial amount of NADPH to continuously reduce cysteine to cystine and maintain intracellular cysteine levels at non-toxic levels. When glucose levels decrease and intracellular NADPH concentration declines, intracellular disul de stress occurs, resulting in signi cant accumulation of cysteine and other disul de compounds, leading to altered protein function and triggering disul dptosis 13 . This emerging form cell death may play a positive role in tumor growth and treatment resistance.…”

Section: Discussionmentioning

confidence: 99%

A disulfidptosis-related LncRNAs index predicting prognosis and tumor microenvironment in colorectal cancer

Xiao,

Yin,

Chen

et al. 2023

Preprint

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Colorectal cancer(CRC) is a common and deadly cancer in the world with a high lethality rate. Disulfidptosis has been found to be an emerging mode of death in cancer, and the purpose of this study to explore the relationship between disulfidptosis-related lncRNAs and CRC, developing a prognostic model for CRC. The gene expression data and clinicopathologic information of colorectal cancer patients was from The Cancer Genome Atlas(TCGA) and screened for disulfidptosis-related lncRNAs based on correlation analysis. Using the least absolute shrinkage and selection operator(LASSO) and Cox regression to construct the prognostic modeling, and its validation was carried out by PCA and receiver operating characteristic(ROC) curves. Also, we constructed the nomograms combining with the model. Finally, the possible mechanisms how to affect CRC by lncRNAs were explored by functional enrichment analysis, immune infiltration and immune escape analysis. In a word, we developed a prognostic marker consisting of lncRNAs associated with disulfidptosis to help clinicians predict the survival of different CRC patients and use different therapies depending on the conditions.

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SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells

Cited by 103 publications

References 53 publications

Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells

Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

A disulfidptosis-related LncRNAs index predicting prognosis and tumor microenvironment in colorectal cancer

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