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| Open AccessAnalysis of human metabolism by reducing the complexity of the genome-scale models using redHUMAN
The complexity of genome-scale metabolic networks (GEMs) hinders their application in specific physiological contexts. Here, the authors introduce a framework to reduce thermodynamically curated GEMs to the subnetworks of interest and demonstrate its application by deriving leukemia-specific models.
- Maria Masid
- , Meric Ataman
- & Vassily Hatzimanikatis
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Article
| Open AccessISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity
The ubiquitin-like modifier ISG15 exerts post-translational protein regulation through ISGylation. Here, the authors show that ISGylation is necessary for pancreatic cancer stem cell self-renewal and tumourigenesis by supporting the recycling of non-functional mitochondria.
- Sonia Alcalá
- , Patricia Sancho
- & Bruno Sainz Jr
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Article
| Open AccessN6-methyladenosine regulates glycolysis of cancer cells through PDK4
Dysregulation of N6-Methyladenosine (m6A) is associated with cancer progression. Here, authors show that m6A methylation of pyruvate dehydrogenase kinase 4 (PDK4) positively regulates its mRNA stability and translation, and consequently affects glycolysis in cancer cells
- Zihan Li
- , Yanxi Peng
- & Hongsheng Wang
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Article
| Open Access2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer
Androgen receptor (AR) signalling regulates cellular metabolism in prostate cancer. Here, the authors perform a proteomics and metabolomics characterisation of prostate cancer cells adapted to long-term resistance to AR inhibition and show rewiring of glucose and lipid metabolism, and further identify a signature associated with resistance to AR inhibition.
- Arnaud Blomme
- , Catriona A. Ford
- & Hing Y. Leung
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Article
| Open AccessSynergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers
Fasting diets are emerging as an approach to delay tumor progression and improve cancer therapies. Here, the authors show that the combination of fasting-mimicking diet with vitamin C decreases tumor development and increases chemotherapy efficacy in KRAS-mutant cancer.
- Maira Di Tano
- , Franca Raucci
- & Valter D. Longo
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| Open AccessFasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression
The molecular mechanisms underpinning how fasting inhibits tumourigenesis are not completely elucidated. Here, the authors show that fasting upregulates the cholesterogenic gene FDFT1 which leads to decreased AKT/mTOR/HIF1a signalling and glycolysis reduction in colorectal cancer.
- Mei-lin Weng
- , Wan-kun Chen
- & Chang-hong Miao
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Article
| Open AccessTRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism
The PI3K/AKT signalling pathway regulates cancer metabolism. Here, the authors show a reciprocal positive feedback crosstalk between the PI3K/AKT and pentose phosphate pathway which promotes tumourigenesis.
- Jie Cheng
- , Yan Huang
- & Hong Wu
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Article
| Open Accessp53-mediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell survival
Cancer cells can produce asparagine, yet both the regulation and biological functions of asparagine are unclear. Here the authors show that p53 suppresses asparagine synthesis and disrupts asparagine-aspartate homeostasis contributing to tumor growth inhibition, and that asparagine and aspartate modulates AMPK-mediated p53 activation by physically binding to and regulating LKB1.
- Longfei Deng
- , Pengbo Yao
- & Peng Jiang
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Article
| Open AccessSubpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion
The presence of phenotypic heterogeneity in collectively invading cells suggests cooperation amongst distinct subtypes of cells to promote invasion and metastasis. Here, the authors use chemical biology tools and report metabolic heterogeneity within the lung cancer collective invasion pack.
- R. Commander
- , C. Wei
- & A. I. Marcus
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Article
| Open AccessLong noncoding RNA AGPG regulates PFKFB3-mediated tumor glycolytic reprogramming
PFKFB3 enhances glycolysis to promote cancer cell proliferation. Here, the authors identify a long noncoding RNA in esophageal squamous cell carcinoma, AGPG, which interacts with PFKFB3 and promotes its stability, leading to increased glycolysis and proliferation.
- Jia Liu
- , Ze-Xian Liu
- & Huai-Qiang Ju
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Article
| Open AccessRac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer
Acquired resistance to chemotherapy can lead to multi-drug resistance and poor prognosis in cancer. Here, the authors show that Rac1 increases glycolysis and non-oxidative pentose phosphate pathway activity leading to neoadjuvant chemotherapy (NAC) resistance, thus its inhibition sensitizes resistant breast cancer PDXs to NAC.
- Qingjian Li
- , Tao Qin
- & Hai Hu
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Article
| Open AccessA shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer
Glucose metabolism is known to be dysregulated in cancer. Here, the authors show that glutamine nitrogen is also affected in cancer and demonstrate that glutaminase 1 and phosphoribosyl pyrophosphate amidotransferase are the key enzymes that control this metabolic switch.
- Manabu Kodama
- , Kiyotaka Oshikawa
- & Keiichi I. Nakayama
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Article
| Open AccessCancer associated fibroblast FAK regulates malignant cell metabolism
Cancer associated fibroblasts (CAFs) have been suggested to regulate cancer cell metabolism, but the mechanisms are not completely elucidated. Here, the authors show that low FAK expression in stromal cells correlates with poor prognosis in breast and pancreatic cancer patients and that FAK-silencing in CAFs promotes tumourigenesis by the paracrine regulation of cancer cell metabolism.
- Fevzi Demircioglu
- , Jun Wang
- & Kairbaan Hodivala-Dilke
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Article
| Open AccessMacropinocytosis confers resistance to therapies targeting cancer anabolism
Macropinocytosis allows cancer cells to cope with nutrient stress. Here, the authors use a selective, genetic approach to inhibit macropinocytosis and show that consuming necrotic cell debris via macropinocytosis—necrocytosis—affords resistance to many therapies that target biosynthesis.
- Vaishali Jayashankar
- & Aimee L. Edinger
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Article
| Open AccessMTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing
Aberrant alternative splicing has been shown to contribute to the tumorigenic processes. Here, the authors show that MTR4 is overexpressed in hepatocellular carcinoma and has a role in tumorigenesis through the modulation of the splicing of glycolytic genes PKM2 and GLUT1.
- Lili Yu
- , Jinchul Kim
- & Yang Xu
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Article
| Open AccessTargeting glutamine metabolism slows soft tissue sarcoma growth
Glutamine is an energetic source required for the proliferation of cancer cells. Here, the authors show that soft tissue sarcomas expressing high levels of glutaminase (GLS) are particularly sensitive to glutamine starvation and GLS inhibition in tumour-bearing allograft and autochthonous mouse models.
- Pearl Lee
- , Dania Malik
- & M. Celeste Simon
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Article
| Open AccessResistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1
There are many patients who do not respond to immune checkpoint inhibitor (ICI) immunotherapy. Here, the authors show a significant negative correlation between sphingosine kinase-1 (SK1) expression and survival for ICI-treated melanoma patients, and further show that targeting SK1 improves response to ICI in mouse cancer models.
- Caroline Imbert
- , Anne Montfort
- & Céline Colacios
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Article
| Open AccessTGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells
The tumour microenvironment is known to have an acidic pH but how this influences cancer cell phenotype is unclear. Here, the authors show that tumour cells upregulate TGF-β2 under acidosis, which leads to the increased formation of lipid droplets allowing for invasiveness and metastases.
- Cyril Corbet
- , Estelle Bastien
- & Olivier Feron
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Article
| Open AccessArf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice
Cancer stem cells (CSC) have been shown as the origin for therapeutic resistance and patient relapse. Here, the authors show that targeting Arf1-mediated lipid metabolism in CSC induces cell death but also an immunogenic anti-cancer response.
- Guohao Wang
- , Junji Xu
- & Steven X. Hou
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Article
| Open AccessO-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth
Post-translational modifications of phosphoglycerate kinase 1 (PGK1), a glycoytic enzyme, contribute to cancer progression. Here, the authors show that PGK1 is O-GlcNAcylated at T255, which induces its translocation into mitochondria to suppress the tricarboxylic acid cycle for colorectal cancer growth.
- Hao Nie
- , Haixing Ju
- & Wen Yi
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Article
| Open AccessPharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy
Prostate cancer cells depend on MTAP, the rate-limiting enzyme involved in the methionine salvage pathway, to cope with increased polyamine biosynthesis. Here, the authors show that inducing upregulation of polyamine biosynthesis and targeting MTAP synergize to increase apoptosis in prostate cancer cells.
- Hayley C. Affronti
- , Aryn M. Rowsam
- & Dominic J. Smiraglia
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Article
| Open AccessReactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer
Glycolysis is elevated in many cancers. In this study, the authors show that lactoylglutathione, a by-product of methylglyoxal produced from increased glycolysis, is elevated in lung cancer in mouse models and humans, arguing reactive metabolite production can be a liability for cancers.
- Alba Luengo
- , Keene L. Abbott
- & Matthew G. Vander Heiden
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Article
| Open AccessAurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect
Aurora-A kinase is frequently over-expressed in tumours. Here, the authors show that it modulates the activity of lactate dehydrogenase B, resulting in enhanced glycolysis, bio-synthesis and tumour growth.
- Aoxing Cheng
- , Peng Zhang
- & Zhenye Yang
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Article
| Open AccessA high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells
Many cancer cells have increased glucose consumption compared to normal cells, a feature that can be exploited therapeutically. Here, the authors carry out a chemical screen and identify compounds that selectively blocks glucose metabolism in non-small-cell lung cancer cell lines.
- Chiara Ghezzi
- , Alicia Wong
- & Peter M. Clark
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Article
| Open AccessEssentiality of fatty acid synthase in the 2D to anchorage-independent growth transition in transforming cells
The mechanisms associated with fatty acid synthase (FASN) upregulation during transformation are unclear. Here, the authors report that FASN promotes anaplerotic shift of the Krebs cycle in cancer cells expressing various oncogenes, and that its inhibition before transformation prevents tumour development and invasion.
- Maria J. Bueno
- , Veronica Jimenez-Renard
- & Miguel Quintela-Fandino
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Article
| Open AccessGenome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC
Resistance to the tyrosine kinase inhibitor Sorafenib, which is the standard treatment for advanced hepatocellular carcinoma, is a major clinical challenge. Here, the authors show that phosphoglycerate dehydrogenase, a key enzyme in the serine synthesis pathway, drives sorafenib resistance.
- Lai Wei
- , Derek Lee
- & Chun-Ming Wong
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Article
| Open AccessHigh-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program
Prostate cancer progression may be enhanced by a high-fat diet. Here the authors show that a diet high in saturated fats enhance the MYC-driven transcriptional program, a feature that independently predicts prostate cancer progression and death.
- David P. Labbé
- , Giorgia Zadra
- & Myles Brown
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Article
| Open AccessCaspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis
Caspases are most closely associated with cell death, but many have other cellular functions. Here, Das et al. find that upon metabolic stress, caspase-10 cleaves ACLY to regulate metabolic homeostasis and epigenetic reprogramming by altering Acetyl-CoA levels.
- Rajni Kumari
- , Ruhi S. Deshmukh
- & Sanjeev Das
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Article
| Open AccessDistinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma
Lung adenocarcinomas frequently harbour KRAS mutations, of which a subset are characterized by co-mutation of KEAP1. Here the authors show, in mice, that KrasG12D mutant tumours are metabolically distinct, with a bronchiolar cell-of-origin.
- Sarah A. Best
- , Sheryl Ding
- & Kate D. Sutherland
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Article
| Open AccessCD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis
CD36 is a membrane glycoprotein that has been shown to have tumour promoting or suppressor function depending on tumour type. Here, the authors address CD36 function in colorectal cancer and show it acts as a tumour suppressor by inhibiting B-catenin/myc signalling, resulting in downregulation of glycolysis.
- Yuan Fang
- , Zhi-Yong Shen
- & Yi Ding
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Article
| Open AccessLiquid biopsy-based single-cell metabolic phenotyping of lung cancer patients for informative diagnostics
Non-invasive methods to predict treatment response are urgently needed. Here in lung cancer, the authors develop a single-cell on-chip cytometry method to metabolically phenotype disseminated tumor cells, revealing metabolic heterogeneity and predictors of therapy response and survival.
- Ziming Li
- , Zhuo Wang
- & Qihui Shi
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Article
| Open AccessMetabolic landscape of the tumor microenvironment at single cell resolution
Each cell type in the tumour microenvironment has unique metabolic demands enabling specific functions. Here the authors use published single-cell RNA-seq data and develop a computational framework to better understand the heterogeneity of tumour metabolism, highlighting the discordance between results obtained from single cells and bulk tumours.
- Zhengtao Xiao
- , Ziwei Dai
- & Jason W. Locasale
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Article
| Open AccessGenotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis
It is known that genotoxic stress induces high levels of ROS and deplete cellular glutathione stores. Here, Cao et al. uncover a β-catenin-dependent TCF/LEF-independent mechanism that promotes histone-mediated transcriptional activation of glutathione synthesis.
- Lixue Cao
- , Geyan Wu
- & Jun Li
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Article
| Open AccessPAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma
Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.
- Melusine Bleu
- , Swann Gaulis
- & Giorgio G. Galli
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Article
| Open AccessMYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat
Genes related to lysosomal and autophagic systems are transcriptionally regulated by the Mit/TFE family of transcription factors. Here the authors show that MYC, in association with HDACs, suppresses the expression of lysosomal and autophagy genes by competing with the Mit/TFE transcription factors for occupancy of their target gene promoters.
- Ida Annunziata
- , Diantha van de Vlekkert
- & Alessandra d’Azzo
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Article
| Open AccessLncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc
lncRNA and cellular metabolism are frequently dysregulated in cancer. In this study, the authors discover the lncGLCC1 is increased in colorectal cancer cells under glucose starvation conditions and correlates with poor prognosis in this cancer.
- Jiayin Tang
- , Tingting Yan
- & Jing-Yuan Fang
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Article
| Open AccessER-residential Nogo-B accelerates NAFLD-associated HCC mediated by metabolic reprogramming of oxLDL lipophagy
Non alcoholic fatty liver disease (NAFLD) associates with an elevated risk of developing hepatocellular carcinoma (HCC). Here, the authors find that Nogo-B, an endoplasmic reticulum resident protein, is upregulated by lipid uptake and acts as an oncogene in NAFLD-associated HCC by promoting lipid droplet breakdown by lipophagy and triggering Hippo pathway dysregulation
- Yuan Tian
- , Bin Yang
- & Pengyuan Yang
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Article
| Open AccessAn ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis
Polycomb Repressor Complex 2 (PRC2) is frequently up-regulated in cancers. Here, the authors show that the tyrosine kinase c-Src stimulates mitochondrial function to signal energy sufficiency to mTORC1, increasing translation of the PRC2 subunits EZH2 and SUZ12 to support ErbB2-dependent tumours.
- Harvey W. Smith
- , Alison Hirukawa
- & William J. Muller
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Article
| Open AccessProbabilistic controllability approach to metabolic fluxes in normal and cancer tissues
Metabolic rewiring is a feature of many cancers. Here, the authors combine control theory and flux correlation analysis to study the transition of healthy metabolic networks to cancer states, and find that cancer metabolism is characterized by more streamlined flux distributions.
- Jean-Marc Schwartz
- , Hiroaki Otokuni
- & Jose C. Nacher
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Article
| Open AccessIdentification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer
Cancer subtypes may have distinct metabolic vulnerabilities that can be exploited for therapeutic interventions. Here, the authors show that in lung cancer, genetic activation of distinct oncogenic receptor tyrosine kinases results in unique metabolic liabilities and, in particular, EGFR aberrant cancers rely on the serine biosynthetic pathway while FGFR aberrant cancers rely on glycolysis.
- Nan Jin
- , Aiwei Bi
- & Min Huang
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Article
| Open AccessMetabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation
Cancer cells must develop distinct metabolic adaptations to survive in challenging metastatic environments. Here, the authors find, via an in vivo RNAi screen, that the aldo-keto reductase AKR1B10 limits the toxic side effects of oxidative stress to sustain fatty acid oxidation and promote metastatic colonisation.
- Antoinette van Weverwijk
- , Nikolaos Koundouros
- & Clare M. Isacke
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Article
| Open AccessNon-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion
Cancer cells develop specific metabolic adaptations. Here, the authors show that in prostate cancer models, the ubiquitin ligase Hect9 promotes tumor growth by accelerating glucose metabolism via ubiquitination of Hexokinase 2, a central regulator of glycolysis.
- Hong-Jen Lee
- , Chien-Feng Li
- & Chia-Hsin Chan
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Article
| Open AccessTranslatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells
The ribosomal protein RPL10 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). Here, the authors show that it promotes proliferation of T-ALL cells by upregulating the serine biosynthesis enzyme phosphoserine phosphatase which in turn modulates serine and glycine metabolism.
- Kim R. Kampen
- , Laura Fancello
- & Kim De Keersmaecker
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Article
| Open AccessMetabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism
Aberrant gene expression in cancer coincides with drastic changes in metabolism. Here, the authors combined metabolome, transcriptome and proteome data in 54 cancer cell lines to uncover a genome-scale network of associations between transcriptional regulators and metabolites.
- Karin Ortmayr
- , Sébastien Dubuis
- & Mattia Zampieri
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Article
| Open AccessA GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.
- Yilong Zou
- , Michael J. Palte
- & Stuart L. Schreiber
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Article
| Open AccessSpatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells
Measuring metabolic fluxes in cellular compartments is a challenge. Here, the authors introduce an approach to infer fluxes in mitochondria and cytosol, and find that IDH1 is the major producer of cytosolic citrate in HeLa cells and that in SDH- deficient cells citrate synthase functions in reverse.
- Won Dong Lee
- , Dzmitry Mukha
- & Tomer Shlomi
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Article
| Open AccessTargeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma
A subset of esophageal squamous cell carcinoma harbors dysregulated Fbxo4- cyclin D1 axis. Here, the authors show that the dysregulation of Fbxo4-cyclin D1 leads to mitochondrial dysfunction and glutamine addiction rendering these tumors susceptible to metabolic inhibitors even when resistant to CDK4/6 inhibitors.
- Shuo Qie
- , Akihiro Yoshida
- & J. Alan Diehl
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Article
| Open AccessABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield
The mechanisms underlying differential chemotherapeutic response to 5-fluorouracil are not fully known. Here, the authors show that ABDH5 regulates sensitivity to 5-fluorouracil in colorectal cancer by regulating lysosome function.
- Juanjuan Ou
- , Yuan Peng
- & Houjie Liang
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Article
| Open AccessTyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance
6-phosphogluconate dehydrogenase is commonly upregulated in cancers. Here, the authors show that activation of EGFR induces phosphorylation of this enzyme at Y481 to activate the pentose phosphate pathway, which consequently reduces ROS and accelerates DNA synthesis to promote tumor growth and radioresistance.
- Ruilong Liu
- , Wenfeng Li
- & Weiwei Yang