MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells

Kuang, Feimei; Liu, Jiao; Xie, Yangchun; Tang, Daolin; Kang, Rui

doi:10.1016/j.chembiol.2021.01.006

Cited by 116 publications

(78 citation statements)

References 72 publications

(88 reference statements)

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“…Further identification of the metabolic sensors responsible for lipid synthesis, oxidation, and degradation will be important to understand the utility of ferroptosis for cancer therapy. Because glucose and lipid metabolism crosstalk at multiple levels (Chen et al, 2019;Saltiel and Kahn, 2001), it will be important to characterize how the metabolic flexibility of cancer cells may modulate ferroptotic responses in pancreatic tumorigenesis and therapy (Badgley et al, 2020;Dai et al, 2020a, Dai et al, 2020bKuang et al, 2021;Liu et al, 2021). Because ferroptosis is a type of autophagy-dependent cell death (Liu et al, 2020;Zhou et al, 2020), it is also important to understand how dysfunctional degradation pathways affect the protein levels of key metabolic regulators during ferroptosis (Chen et al, 2021c;Hou et al, 2016;Hu et al, 2021;Li et al, 2021).…”

Section: Cell Reportsmentioning

confidence: 99%

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

et al. 2021

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Section: Cell Reportsmentioning

confidence: 99%

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

et al. 2021

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“…Ferroptosis sensitivity is governed by several transcription factors, including p53 (36-38), YAP1/TAZ (39,40), and NFE2L2 (8)(9)(10)(11). Here we show that the NGLY1/NFE2L1 pathway can also antagonize ferroptosis, in parallel to the related KEAP1/NFE2L2 pathway.…”

Section: Discussionmentioning

confidence: 57%

“…Vertebrates express four CNC family transcription factors, including the related NFE2L1 (NRF1) and NFE2L2 (NRF2) proteins. NFE2L2 is considered the master 'antioxidant' transcription factor and can inhibit ferroptosis by regulating the expression of the cystine transporter subunit SLC7A11, glutamate-cysteine ligase (GCL) subunits GCLC and GCLM, and other effectors (8)(9)(10)(11)(12)(13)(14)(15). Interestingly, however, Nfe2l2 is not essential for development in mice, and adult animals exhibit only minor phenotypic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis Regulation by the NGLY1/NFE2L1 Pathway

Forcina

Pope

Murray

et al. 2021

Preprint

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Ferroptosis is an oxidative form of non-apoptotic cell death whose transcriptional regulation is poorly understood. Cap'n'collar (CNC) transcription factors including Nuclear Factor Erythroid-2 Related Factor 1 (NFE2L1/NRF1) and NFE2L2 (NRF2) are important regulators of oxidative stress responses. Here, we report that NFE2L1 expression inhibits ferroptosis, independent of NFE2L2. NFE2L1 inhibits ferroptosis by promoting expression of the key anti-ferroptotic lipid hydroperoxidase glutathione peroxidase 4 (GPX4). NFE2L1 abundance and function are regulated post-translationally by N-glycosylation. Functional maturation of NFE2L1 requires deglycosylation by cytosolic peptide:N-glycanase 1 (NGLY1). We find that loss of NGLY1 or NFE2L1 enhances ferroptosis sensitivity. Expression of wild-type NGLY1 but not a disease-associated NGLY1 mutant inhibits ferroptosis, and this effect is dependent on the presence of NFE2L1. Enhanced ferroptosis sensitivity in NFE2L1 and NFE2L2 knockout cells can be potently reverted by expression of an NFE2L1 mutant containing eight asparagine-to-aspartate protein sequence substitutions, which mimic NGLY1-catalyzed sequence editing. Enhanced ferroptosis sensitivity in NGLY1/NFE2L1 pathway mutants could also be reversed by overexpression of NFE2L2. These results suggest that ferroptosis sensitivity is regulated by NGLY1-catalyzed NFE2L1 deglycosylation, and highlight a broad role for CNC transcription factors in ferroptosis regulation.

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“…Pharmacological repression of ALOX5 protected neurons from ferroptosis in mice with stroke ( Karuppagounder et al, 2018 ). ALOX5 inhibition limited lipid peroxidation during ferroptosis and indirectly promoted the growth of pancreatic cancer cells ( Kuang et al, 2021 ). Our study showed that ALOX5 may improve survival rates in melanoma by inducing ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

A Ferroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Cutaneous Melanoma

Chen

2021

Front. Genet.

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BackgroundCutaneous melanoma is a common but aggressive tumor. Ferroptosis is a recently discovered cell death with important roles in tumor biology. Nevertheless, the prognostic power of ferroptosis-linked genes remained unclear in cutaneous melanoma.MethodsCutaneous melanoma patients of TCGA (The Cancer Genome Atlas) were taken as the training cohort while GSE65904 and GSE22153 as the validation cohorts. Multifactor Cox regression model was used to build a prognostic model, and the performance of the model was assessed. Functional enrichment and immune infiltration analysis were used to clarify the mechanisms.ResultsA five ferroptosis-linked gene predictive model was developed. ALOX5 and GCH1 were illustrated as independent predictive factors. Functional assessment showed enriched immune-linked cascades. Immune infiltrating analysis exhibited the distinct immune microenvironment.ConclusionHerein, a novel ferroptosis-related gene prognostic model was built in cutaneous melanoma. This model could be used for prognostic prediction, and maybe helpful for the targeted and immunotherapies.

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MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells

Cited by 116 publications

References 72 publications

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

Ferroptosis Regulation by the NGLY1/NFE2L1 Pathway

A Ferroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Cutaneous Melanoma

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