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| 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
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Article
| Open AccessInducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses
Lack of respiratory complex I is a hallmark of oncocytomas. Here the authors show that inactivation of this complex via knockout of the NDUFS3 subunit or using metformin, converts tumors from an aggressive phenotype into low-proliferative oncocytomas, which can be further inhibited by targeting pro-tumorigenic macrophages.
- Ivana Kurelac
- , Luisa Iommarini
- & Giuseppe Gasparre
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Article
| Open AccessKindlin-2 links mechano-environment to proline synthesis and tumor growth
The mechano-properties of the Extracellular Matrix (ECM) are important for tumorigenesis. Here, the authors show that the stiffening of the ECM promotes translocation of the focal adhesion protein—Kindlin-2—to the mitochondria, where it interacts with the proline synthesis enzyme PYCR1, stimulating proline synthesis and cell proliferation.
- Ling Guo
- , Chunhong Cui
- & Chuanyue Wu
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Article
| Open AccessMiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1
Pancreatic ductal adenocarcinoma must adapt to a nutrient-poor microenvironment. Here, the authors show that miR-135 accumulates in response to glutamine deprivation and inhibits aerobic glycolysis by targeting phosphofructokinase-1, thereby redirecting glucose carbon to the TCA cycle and allowing pancreatic cancer cells survival.
- Ying Yang
- , Mari B. Ishak Gabra
- & Mei Kong
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Article
| Open AccessCentral body fatness is a stronger predictor of cancer risk than overall body size
Obesity is linked to increased cancer risk but the impact of body size versus weight distribution in determining the increased risk is unclear. Here the authors examined body mass index, waist circumference, and waist to hip ratio in relation to all-cancer incidence and incidence of seven individual cancers in a population of approximately 26,000 individual and conclude that central adiposity appears to be a stronger predictor of all-cancer risk than body size.
- Amanda M. Barberio
- , Asalah Alareeki
- & Darren R. Brenner
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Article
| Open AccessCoordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia
Glutamine metabolism is increased in proliferating cells under hypoxia potentially generating exceeding nitrogen. Here the authors show that under hypoxia a specific metabolic pathway is activated to push glutamine carbons and excess nitrogen via the reductive pathway to dihyroorotate which is then secreted by the cells and that such pathway is necessary for tumor growth.
- Yuanyuan Wang
- , Changsen Bai
- & Binghui Li
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Article
| Open AccessIncreased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin
Most tumours are characterized by increased aerobic glycolytic activity. Here the authors show that elevated aerobic glycolysis is not essential for cancer initiation by testing the effect of lactate dehydrogenase depletion on the ability of hair follicle stem cells (HFSCs) to form squamous cell carcinoma (SCC) in mouse genetic models.
- A. Flores
- , S. Sandoval-Gonzalez
- & W. E. Lowry
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Article
| Open AccessA chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition
Cancer cells are metabolically adaptable and the identification of specific vulnerabilities is challenging. Here the authors identify a subset of neuroendocrine cell lines exquisitely sensitive to inhibition of SQLE, an enzyme in the cholesterol biosynthetic pathway, due to the toxic accumulation of pathway intermediate squalene.
- Christopher E. Mahoney
- , David Pirman
- & Gromoslaw A. Smolen
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Article
| Open AccessThe mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis
TOP1MT is a topoisomerase that is localised to mitochondria. Here, the authors show that TOP1MT has a tumor promoting role in hepatocellular carcinoma by supporting mitochondrial translation and that its deficiency limits tumorigenicity.
- S. A. Baechler
- , V. M. Factor
- & Y. Pommier
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Article
| Open AccessAn inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men. Here the authors find a potential mechanistic explanation by showing that, in mice, obesity-induced STAT3 cooperates with the androgen receptor to activate the mTORC pathway through up regulation of CCRK, resulting in hepatic steatosis worsening and HCC development via metabolic and immune reprogramming.
- Hanyong Sun
- , Weiqin Yang
- & Alfred S. L. Cheng
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Article
| Open AccessCaveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy
Trastuzumab binding to tumor cells depends on the availability of HER2 at the cell membrane. Here the authors show that caveolin-1 (CAV1) regulates HER2 density at the cell membranes and that CAV1 gene knockdown or protein depletion via the cholesterol modulator lovastatin, increases trastuzumab binding and anti-tumor activity.
- Patrícia M. R. Pereira
- , Sai Kiran Sharma
- & Jason S. Lewis
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Article
| Open AccessInterplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy
Prostate cancer often develops resistance to androgen receptor (AR) targeting drugs. Here, the authors show that, under conditions of hypoxia, AR inhibition via enzalutamide increases the expression of the glycolytic enzyme phosphoglucose isomerase (GPI) promoting a metabolic rewiring that allows the cells to survive, and consistent GPI inhibition restores sensitivity to enzalutamide.
- Hao Geng
- , Changhui Xue
- & David Z. Qian
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Article
| Open AccessOncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis
Pancreatic ductal adenocarcinoma (PDAC) cells display varying degrees of reliance on oncogenic KRAS. Here the authors show that KRAS-resistant PDAC cells maintain nucleotides synthesis through a KRAS-independent upregulation of the non-oxidative pentose phosphate pathway gene RPIA and that targeting nucleotide metabolism restore sensitivity to KRAS pathway inhibition.
- Naiara Santana-Codina
- , Anjali A. Roeth
- & Alec C. Kimmelman
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Article
| Open AccessTAp73-induced phosphofructokinase-1 transcription promotes the Warburg effect and enhances cell proliferation
TAp73 is a structural homolog of the tumor suppressor p53. Here they show that TAp73 is critical for promoting glycolysis as it stimulates the transcriptional expression of liver type of phosphofructokinase-1 (PFKL), which catalyzes the committed step in glycolysis.
- Le Li
- , Lijia Li
- & Peng Jiang
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Article
| Open AccessDeacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
Serine hydroxymethyltransferase 2 (SHMT2) converts serine to glycine in mitochondria and is upregulated in a variety of cancers. Here the authors show that acetylation of the lysine-95 (K95) residue negatively regulates SHMT2 expression and activity and is deacetylated by SIRT3 in colorectal cancer.
- Zhen Wei
- , Jinglue Song
- & Wei Yu
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Article
| Open AccessNuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth
High-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and current evidences link E7 to HPV-associated carcinogenesis. Here the authors propose a model in which the infection of epithelial cells with high risk HPV results in a burst of reactive oxygen species, translocation of LDHA to the nucleus and activation of a gene profile that supports the growth of cervical cancer.
- Yuan Liu
- , Ji-Zheng Guo
- & Qun-Ying Lei
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Article
| Open AccessBiosynthetic energy cost for amino acids decreases in cancer evolution
Proliferating cancer cells have a high demand for amino acids. Here, Zhang et al. show that cancer cells evolve towards gene expression profiles that use amino acids with lower biosynthetic energy costs, and demonstrate the potential prognostic utility of quantifying the extent of this adaptation.
- Hong Zhang
- , Yirong Wang
- & Jian Lu
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Article
| Open AccessMitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers
Several challenges are involved in direct targeting of mutant p53, while targeting altered fitness of cells with loss of wild type p53 is an alternative approach. Here they identify niclosamide to be selectively toxic to p53 deficient cells through a previously unknown mitochondrial uncoupling mechanism.
- R. Kumar
- , L. Coronel
- & C. F. Cheok
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Article
| Open AccessTargeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
Targeting the glycolytic PFKFB3 enzyme is being studied as a therapeutic strategy against cancer. Here the authors identify PFKFB3 as being involved in homologous recombination (HR) repair of DNA double strand breaks (DSBs) and present a PFKFB3 inhibitor.
- Nina M. S. Gustafsson
- , Katarina Färnegårdh
- & Thomas Helleday
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Article
| Open AccessSystems analysis of intracellular pH vulnerabilities for cancer therapy
Tumors often exhibit a pH gradient, with an acidic extracellular space and alkaline cytoplasm. Here the authors develop a computational model to show how alkaline pHi supports changes inherent to cancer cell metabolism and acidification disables these adaptations, and demonstrate the effect of acidic pHi on breast cancer cell survival.
- Erez Persi
- , Miquel Duran-Frigola
- & Eytan Ruppin
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Article
| Open AccessArf6-driven cell invasion is intrinsically linked to TRAK1-mediated mitochondrial anterograde trafficking to avoid oxidative catastrophe
Mitochondria subcellular localization is dynamically regulated during migration. Here, the authors show that Arf6–AMAP1 dependent ILK localization at focal adhesions reduces mitochondrial retrograde trafficking in migratory cells and prevents mitochondrial aggregation and detrimental ROS production.
- Yasuhito Onodera
- , Jin-Min Nam
- & Hisataka Sabe
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Article
| Open AccessSustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy
Melanoma patients harbouring BRAFV600E mutation generally develop resistance to targeted therapy. In this study, the authors demonstrate that SREBP-1-mediated induction of lipid biosynthesis contributes to therapy resistance in BRAF mutant melanoma.
- Ali Talebi
- , Jonas Dehairs
- & Johannes V. Swinnen
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Article
| Open AccessDysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors
Mitochondrial dynamics regulate critical processes. Here the authors show that genes regulating mitochondrial dynamics are frequently amplified in human cancers, and that these alterations are associated with changes in drug sensitivity including increased sensitivity to the apoptosis-targeting Smac mimetics.
- Gray R. Anderson
- , Suzanne E. Wardell
- & Kris C. Wood
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Article
| Open AccessGold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival
Surface-enhanced Raman spectroscopy (SERS) visualizes fingerprints of intermolecular vibrations of many metabolites. Here the authors report a SERS imaging technique that enables the visualization of metabolites distribution and automated extraction of tumour boundaries in frozen tissues.
- Megumi Shiota
- , Masayuki Naya
- & Makoto Suematsu
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Article
| Open AccessHOXA9 inhibits HIF-1α-mediated glycolysis through interacting with CRIP2 to repress cutaneous squamous cell carcinoma development
Hypoxia-inducible transcription factor HIF-1α promotes glycolysis allowing cell survival under stress. Here the authors show, using both cell lines and animal models, that in cutaneous squamous cell carcinoma HOXA9 acts as a tumor suppressor and inhibits glycolysis by associating with CRIP2 to repress HIF-1α binding to target genes.
- Liang Zhou
- , Yinghui Wang
- & Zhenhua Ding
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Article
| Open AccessIncreased formate overflow is a hallmark of oxidative cancer
Serine catabolism to formate supplies one-carbon units for biosynthesis. Here the authors show that formate production in murine cancers with high oxidative metabolism exceeds the biosynthetic demand and that high formate levels promotes invasion of cancer cells.
- Johannes Meiser
- , Anne Schuster
- & Alexei Vazquez
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Article
| Open AccessInterruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects
Tumor cells can fuel their metabolism with lactate. Here the authors show that inhibition of mitochondrial pyruvate carrier (MPC) blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation and inhibits oxidative metabolism, ultimately resulting in cytotoxicity and radiosensitization.
- Cyril Corbet
- , Estelle Bastien
- & Olivier Feron
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Article
| Open AccessSirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner
Tumour metabolism can be controlled through post-translational modifications. Here the authors show that Sirtuin5 promotes glutaminolysis in colorectal cancer cells via glutamate dehydrogenase-1, a critical regulator of glutaminolysis, inducing its deglutarylation and functional activation.
- Yun-Qian Wang
- , Hao-Lian Wang
- & Jing-Yuan Fang
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Article
| Open AccessAcetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis
Enhanced glycolysis in cancer cells has been associated with protection from DNA damage. Here the authors show that DNA damaging signals induce acetylation of PFKFB3 at lysine K472 and promote its cytosolic accumulation, which enhances glycolysis, resulting in protection from cisplatin-induced cell death.
- Fu-Long Li
- , Jin-Ping Liu
- & Hai-Xin Yuan
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Article
| Open AccessHexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin
Hexokinase 2 (HK2) is selectively upregulated in hepatocellular carcinoma (HCC). Here the authors show that HK2 ablation decreases glycolysis and triggers oxidative phosphorylation (OXPHO) rendering HCC more susceptible to the OXPHO inhibitor metformin and to the FDA-approved drug sorafenib.
- Dannielle DeWaal
- , Veronique Nogueira
- & Nissim Hay
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Article
| Open AccessLysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance
Lipid droplets (LD) accumulation correlates with colorectal cancer (CRC) relapse. Here the authors show that chemotherapy induces LD synthesis via acyltransferase LPCAT2 which, in turn, promotes chemoresistance via LD accumulation both in vitro and in vivo by blocking chemotherapy-induced ER stress.
- Alexia Karen Cotte
- , Virginie Aires
- & Dominique Delmas
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Article
| Open AccessStructural characterisation reveals insights into substrate recognition by the glutamine transporter ASCT2/SLC1A5
Cancer cells are reliant on nutrients such as glutamine, which enter the cell via the alanine/serine/cysteine transporter 2 (ASCT2). Here, authors use crystallography to show which amino-acid residues in the substrate-binding site are responsible for conferring glutamine selectivity to ASCT2.
- Amanda J Scopelliti
- , Josep Font
- & Renae M Ryan
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Article
| Open AccessGlutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells
Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to stimulate matrix metalloproteases recycling to the cell surface.
- Emmanuel Dornier
- , Nicolas Rabas
- & Jim C. Norman
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Article
| Open AccessHIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism
Clear cell renal cancers (ccRCC) display elevated intracellular lipid storage. Here the authors show that such lipid accumulation is due to the repression of carnitine palmitoyltransferase 1A (CPT1A) enzyme that impairs fatty acid (FA) transport into the mitochondrion resulting in reduced FA beta oxidation.
- Weinan Du
- , Luchang Zhang
- & Scott M. Welford
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Article
| Open AccessEpigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival
Cachexia is a metabolic syndrome leading to muscle and adipose tissue loss in majority of cancer patients. Here the authors show that, in a mouse model, BET inhibitor JQ1 counteracts muscle and adipose tissue wasting tempering cachexia and prolonging survival through a mechanism unrelated to tumour growth.
- Marco Segatto
- , Raffaella Fittipaldi
- & Giuseppina Caretti
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Article
| Open AccessNoninvasive liquid diet delivery of stable isotopes into mouse models for deep metabolic network tracing
Isotope tracer administration for probing metabolism in vivo is important to assess metabolic functions in a relevant physiological setting. Here, the authors report a non-invasive method of administering 13C6- glucose to mouse models via liquid diet feeding to achieve deep metabolic network coverage.
- Ramon C. Sun
- , Teresa W.-M. Fan
- & Ye Yang
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Article
| Open AccessPolo-like kinase 1 coordinates biosynthesis during cell cycle progression by directly activating pentose phosphate pathway
Polo-like kinase 1 (Plk1) is a key regulator of mitosis. Here, the authors show that Plk1 activates the pentose phosphate pathway in cancer cells by directly phosphorylating glucose-6-phosphate dehydrogenase (G6PD) and that such activation is critical for cell cycle progression and cancer cell growth.
- Xiaoyu Ma
- , Lin Wang
- & Huafeng Zhang
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Article
| Open AccessNOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance
NADPH oxidase NOX4 has been linked to poor cancer survival. Here the authors show that NOX4 regulates drug resistance in renal cancer carcinoma by regulating PKM2 and that NOX4 activity is allosterically activated by reduced mitochondrial ATP levels thus coupling energy metabolism to drug resistance.
- Karthigayan Shanmugasundaram
- , Bijaya K. Nayak
- & Karen Block
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Article
| Open AccessA novel Fer/FerT targeting compound selectively evokes metabolic stress and necrotic death in malignant cells
The tyrosine-kinases Fer/FerT associate with the mitochondrial electron transport chain in cancer cells supporting their metabolic reprogramming. Here the authors discover a compound that disrupts Fer /FerT activity and selectively induces cell death of cancer cell lines displaying anti-tumor activity in vivo.
- Yoav Elkis
- , Moshe Cohen
- & Uri Nir
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Article
| Open AccessStabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis
Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis. Here the authors show that PFK1 platelet isoform is upregulated in Glioblastoma and is required for tumor growth mechanistically, such upregulation is due to an increased stability induced by AKT activation via phosphorylation on residue S386.
- Jong-Ho Lee
- , Rui Liu
- & Zhimin Lu