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

Lee, Jaewang; Roh, Jong–Lyel

doi:10.3390/antiox11122444

Cited by 49 publications

(37 citation statements)

References 105 publications

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“…77 The SLC7A11-ALOX12 axis is independent of GSH level and the antioxidant activity of GPX4. 78,79 In our study, the suppression of SLC7A11 and GPX4 was observed as well as the reduction of GSH biogenesis, which are convincing and solid evidence that lepadins E and H induce ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Additionally, lepadins E and H were found to increase ACSL4 protein expression, indicating the upregulation of ACSL4 may also contribute to the ferroptosis of Hela cells.…”

Section: Discussionsupporting

confidence: 83%

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Wang,

Ma,

Cheung

et al. 2023

J. Med. Chem.

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Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.

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Section: Discussionsupporting

confidence: 83%

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Wang,

Ma,

Cheung

et al. 2023

J. Med. Chem.

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“…SLC7A11 helps counteract oxidative stress and inhibit ferroptosis by maintaining cellular GSH levels. Studies have shown that high expression of SLC7A11 is closely related to cisplatin resistance in bladder cancer ( 51 , 52 ). Experimental and bioinformatics studies have also demonstrated that the level of SLC3A2 protein is significantly elevated in bladder cancer tumor cells compared to non-cancerous bladder epithelial cells, suggesting that SLC3A2 may serve as a useful tumor tissue marker for the diagnosis of bladder cancer patients ( 53 – 55 ).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk of disulfidptosis-related subtypes, establishment of a prognostic signature and immune infiltration characteristics in bladder cancer based on a machine learning survival framework

et al. 2023

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BackgroundBladder cancer (BLCA) is the most common malignancy of the urinary tract. On the other hand, disulfidptosis, a mechanism of disulfide stress-induced cell death, is closely associated with tumorigenesis and progression. Here, we investigated the impact of disulfidptosis-related genes (DRGs) on the prognosis of BLCA, identified various DRG clusters, and developed a risk model to assess patient prognosis, immunological profile, and treatment response.MethodsThe expression and mutational characteristics of four DRGs were first analyzed in bulk RNA-Seq and single-cell RNA sequencing data, IHC staining identified the role of DRGs in BLCA progression, and two DRG clusters were identified by consensus clustering. Using the differentially expressed genes (DEGs) from these two clusters, we transformed ten machine learning algorithms into more than 80 combinations and finally selected the best algorithm to construct a disulfidptosis-related prognostic signature (DRPS). We based this selection on the mean C-index of three BLCA cohorts. Furthermore, we explored the differences in clinical characteristics, mutational landscape, immune cell infiltration, and predicted efficacy of immunotherapy between high and low-risk groups. To visually depict the clinical value of DRPS, we employed nomograms. Additionally, we verified whether DRPS predicts response to immunotherapy in BLCA patients by utilizing the Tumour Immune Dysfunction and Rejection (TIDE) and IMvigor 210 cohorts.ResultsIn the integrated cohort, we identified several DRG clusters and DRG gene clusters that differed significantly in overall survival (OS) and tumor microenvironment. After the integration of clinicopathological features, DRPS showed robust predictive power. Based on the median risk score associated with disulfidptosis, BLCA patients were divided into low-risk (LR) and high-risk (HR) groups, with patients in the LR group having a better prognosis, a higher tumor mutational load and being more sensitive to immunotherapy and chemotherapy.ConclusionOur study, therefore, provides a valuable tool to further guide clinical management and tailor the treatment of BLCA patients, offering new insights into individualized treatment.

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“…More broadly, we found that ME with heavy glial/vascular contributions increased considerably toward the lesion edge when ME19 and 13 decreased drastically from their peak at the lesion core ( Fig2E ). For example, genes that suppress ferroptosis ( AIFM2 , MGST1 , (62,63)) are enriched in ME19, 13, 8, 18 ( FigS7 ), whereas genes that induce ferroptosis ( SLC7A11 , TMEM164 , (64,65)) are expressed by AST, VLMC, and ependyma of ME group iv, which is significantly enriched in perilesional WM compared to intralesional WM ( FigS5C ). Together, this suggests a transition from immune (intralesional WM) to glial/vascular (perilesional WM)-dominant ME with a mixture of destructive and protective signals as lesions evolve, and we further deconvolute this complexity in the following sections.…”

Section: Mainmentioning

confidence: 99%

A 4D transcriptomic map for the evolution of multiple sclerosis-like lesions in the marmoset brain

Lin,

Brake,

Donadieu

et al. 2023

Preprint

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Single-time-point histopathological studies on postmortem multiple sclerosis (MS) tissue fail to capture lesion evolution dynamics, posing challenges for therapy development targeting development and repair of focal inflammatory demyelination. To close this gap, we studied experimental autoimmune encephalitis (EAE) in the common marmoset, the most faithful animal model of these processes. Using MRI-informed RNA profiling, we analyzed ∼600,000 single-nucleus and ∼55,000 spatial transcriptomes, comparing them against EAE inoculation status, longitudinal radiological signals, and histopathological features. We categorized 5 groups of microenvironments pertinent to neural function, immune and glial responses, tissue destruction and repair, and regulatory network at brain borders. Exploring perilesional microenvironment diversity, we uncovered central roles of EAE-associated astrocytes, oligodendrocyte precursor cells, and ependyma in lesion formation and resolution. We pinpointed imaging and molecular features capturing the pathological trajectory of WM, offering potential for assessing treatment outcomes using marmoset as a platform.One sentence summaryA cross-modality study to identify the spatiotemporal-based diversity of primate brain cells during white matter inflammatory demyelination to inform lesion detection, stratification, and management in multiple sclerosis.

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

Cited by 49 publications

References 105 publications

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Crosstalk of disulfidptosis-related subtypes, establishment of a prognostic signature and immune infiltration characteristics in bladder cancer based on a machine learning survival framework

A 4D transcriptomic map for the evolution of multiple sclerosis-like lesions in the marmoset brain

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