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| Open AccessThe cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells
High cholesterol is a risk factor for breast cancer recurrence. Here the authors show that cholesterol promotes breast cancer metastasis via its metabolite 27-hydroxycholesterol (27HC) that acts on immune myeloid cells residing at the distal metastatic sites, thus promoting an immune suppressive environment.
- Amy E. Baek
- , Yen-Rei A. Yu
- & Erik R. Nelson
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Article
| Open AccessEnergy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development
FoxO are commonly down-regulated transcription factors and tumor suppressors in renal cell cancer (RCC). Here, the authors show that upon energy stress FoxOs induce the expression of the long non-coding RNA FILNC1, which inhibits survival of RCC by downregulating c-Myc and c-Myc-dependent metabolic rewiring.
- Zhen-Dong Xiao
- , Leng Han
- & Boyi Gan
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Article
| Open AccessEnoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients
Overnutrition has been linked to increased risk of cancer. Here, the authors show that exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation.
- Ya-Kun Zhang
- , Yuan-Yuan Qu
- & Wei Xu
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Article
| Open AccessAn in-silico approach to predict and exploit synthetic lethality in cancer metabolism
Exploiting synthetic lethality is a promising approach for cancer therapy. Here, the authors present an approach to identifying such interactions by finding genetic minimal cut sets (gMCSs) that block cancer proliferation, and apply it to study the lethality of RRM1 inhibition in multiple myeloma.
- Iñigo Apaolaza
- , Edurne San José-Eneriz
- & Francisco J. Planes
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Article
| Open AccessRETRACTED ARTICLE: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer
Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors.
- Anthony Alioui
- , Julie Dufour
- & Silvère Baron
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Article
| Open AccessCritical role for arginase 2 in obesity-associated pancreatic cancer
Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Here the authors show that obesity induces the expression of the mitochondrial form of arginase ARG2 in PDA and that ARG2 silencing or loss results in ammonia accumulation and suppression of obesity-driven PDA tumor growth.
- Tamara Zaytouni
- , Pei-Yun Tsai
- & Nada Y. Kalaany
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Article
| Open AccessCollagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions
Cancer cells adapt their metabolism to survive limited nutrient availability. Here, the authors show that in conditions of limited glucose or glutamine availability, pancreatic ductal adenocarcinoma cells can use collagen-derived proline to foster the TCA cycle and allow cell survival bothin vitro and in vivo.
- Orianne Olivares
- , Jared R. Mayers
- & Sophie Vasseur
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Article
| Open AccessMembrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression
LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Here the authors show that LKB1 activation requires direct binding to phospholipids and show this has an implication for carcinogenesis.
- Giada Dogliotti
- , Lars Kullmann
- & Michael P. Krahn
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Article
| Open AccessThe distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition
Adenocarcinoma and squamous cell carcinoma are distinct subtypes of non-small cell lung cancer. Here, the authors show that increased glycolytic flux, via increased glucose transporter Glut1 expression, is a core metabolic feature of squamous cell carcinoma that renders it sensitive to glycolysis inhibition.
- Justin Goodwin
- , Michael L. Neugent
- & Jung-whan Kim
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Article
| Open AccessMICU1 drives glycolysis and chemoresistance in ovarian cancer
The mitochondrial uniporter MICU1 regulates mitochondrial Ca2+ uptake. Here, the authors show that MICU1 is upregulated in ovarian cancer and confers resistance to cisplatin-induced apoptosis through a Ca2+-mediated regulation of pyruvate dehydrogenase activity that results in increased glycolysis.
- Prabir K. Chakraborty
- , Soumyajit Banerjee Mustafi
- & Priyabrata Mukherjee
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Article
| Open AccessAdenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation
Targeting the specific metabolic phenotypes of colorectal cancer stem cells (CRCSCs) is a potential therapeutic strategy for colorectal cancer (CRC). Here, the authors show that adenylate kinase hCINAP is overexpressed in CRC, binds to the C-terminal domain of LDHA and its depletion inhibits invasion, self-renewal, tumorigenesis and chemoresistance of CRCSCs.
- Yapeng Ji
- , Chuanzhen Yang
- & Xiaofeng Zheng
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Article
| Open AccessProline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells
Metastasizing cancer cells rewire their metabolism to support their malignant phenotypes. Here, the authors show that the acquisition of a metastatic phenotype in breast cancer cell lines results in increased proline catabolism and that inhibition of this pathway decreases lung metastasis formation in two mouse models.
- Ilaria Elia
- , Dorien Broekaert
- & Sarah-Maria Fendt
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Article
| Open AccessThe essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis
Yap is a transcriptional factor involved in tumorigenesis. Here the authors show that a previously unknown post-translational modification of Yap, O-GlcNAcylation, increases its transcriptional activity and is required for high glucose-induced liver cancer development.
- Xiao Zhang
- , Yongxia Qiao
- & Fenyong Sun
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Article
| Open AccessInhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival
The lipogenic pathway is often upregulated in liver tumours and regarded as a therapeutic target. Here, the authors show instead that blocking lipogenesis via knockout of acetyl-CoA carboxylase genes results in increased susceptibility to liver tumorigenesis associated with an increased antioxidant defence.
- Marin E. Nelson
- , Sujoy Lahiri
- & Kyle L. Hoehn
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Article
| Open AccessAdipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via β-hydroxybutyrate
Invasion of the adipose tissue correlates with poor prognosis in breast cancer. Here, the authors show that mammary gland adipocytes promote malignancy via β-hydroxybutyrate, which acts on cancer cells through the monocarboxylate transporter MCT2 resulting in tumour-promoting epigenetic modifications.
- Chun-Kai Huang
- , Po-Hao Chang
- & Wen-Hwa Lee
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Article
| Open AccessNur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation
Gluconeogenesis is downregulated in hepatocellular carcinoma. Here, the authors show that nuclear receptor Nur77 acts as a tumour suppressor sustaining gluconeogenesis by enhancing phosphoenolpyruvate carboxykinase (PEPCK1) stability via regulating its interaction with the SUMO-conjugating enzyme Ubc9.
- Xue-li Bian
- , Hang-zi Chen
- & Qiao Wu
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| Open AccessMutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma
Kras activation and p16 inactivation cooperatively promote pancreatic cancer progression. Here, the authors show that such cooperation depends upon an increased expression of the NAD(P)H oxidase NOX4 achieved through transcription factors independently regulated by the two oncogenic genetic alterations.
- Huai-Qiang Ju
- , Haoqiang Ying
- & Paul J. Chiao
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Article
| Open AccessSnail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress
Cancer cell survival under metabolic stress is a critical step for metastasis. Here, the authors show that under glucose deprivation, Snail, a key regulator of the metastatic process, promotes survival by diverting glucose to the pentose phosphate pathway through repression of phosphofructokinase PFKP.
- Nam Hee Kim
- , Yong Hoon Cha
- & Hyun Sil Kim
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| Open AccessmTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation
Inhibitors of the mTORC1 pathway are considered anti-cancer drugs. Here, the authors show that on nutrient restriction, glutaminolysis-induced activation of mTORC1 induces apoptosis via inhibiting autophagy, highlighting that under such conditions inhibition of mTORC1 results in survival of cancer cells.
- Victor H. Villar
- , Tra Ly Nguyen
- & Raúl V. Durán
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Article
| Open Accessc-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis
The protein tyrosine kinase c-Src is a renowned proto-oncogene with pleiotropic effects. Here, the authors show that c-Src induces the metabolic reprogramming of cancer cells by phosphorylating hexokinases HK1 and HK2, which in turns lead to increased HK catalytic activity and consequent enhancement of glycolysis.
- Jia Zhang
- , Suili Wang
- & Qinxi Li
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Article
| Open AccessIntegrative modelling of tumour DNA methylation quantifies the contribution of metabolism
Altered DNA methylation is a feature of cancer and between-patient variability is prevalent. Here, the authors integrate data on thousands of human tumours, and find that expression levels of methionine metabolism genes are predictive of methylation features, and that the breakdown of this relationship is a negative prognostic marker.
- Mahya Mehrmohamadi
- , Lucas K. Mentch
- & Jason W. Locasale
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Article
| Open AccessAmplification of USP13 drives ovarian cancer metabolism
Cancer cells need to reprogramme their metabolism to allow rapid cell proliferation. Here, the authors show that USP13is amplified in ovarian cancer and its protein product, a deubiquitinase, drives tumour progression by rewiring the metabolism of cancer cells by stabilising two critical metabolic enzymes.
- Cecil Han
- , Lifeng Yang
- & Xiongbin Lu
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Article
| Open AccessTissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival
Cancer cells reprogramme their metabolism with unclear clinical implications. Here, the authors analyse the expression of metabolic genes across 20 types of solid cancers and find that clinical aggressiveness, poor survival and metastasis are associated with the deregulation of mitochondrial metabolism.
- Edoardo Gaude
- & Christian Frezza
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Article
| Open AccessThe oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
Oncogenic mutations of isocitrate dehydrogenases 1 and 2 result in the production of the oncometabolite R-2-hydroxyglutarate. Here the authors show that the oncometabolite promotes mTOR activation in a PTEN/PI3K-independent manner by regulating DEPTOR stability via inhibition of KDM4A activity.
- Mélissa Carbonneau
- , Laurence M. Gagné
- & Frédérick A. Mallette
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Article
| Open AccessTargeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia
Chemerin is an adipokine often downregulated in tumours. Here the authors show that chemotherapy induces chemerin production by endothelial cells, leading to cachexia, and that VEGF ablation in myeloid cells prevents cachexia in a chemerin-dependent manner, and improves chemotherapeutic effects.
- Ralph Klose
- , Ewelina Krzywinska
- & Christian Stockmann
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Article
| Open AccessRegulation of energy homeostasis by the ubiquitin-independent REGγ proteasome
In conditions of energy stress cells reduce transcription of ribosomal RNA (rRNA) to maintain cell survival. Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.
- Lianhui Sun
- , Guangjian Fan
- & Chuangui Wang
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Article
| Open AccessPKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis
Protein phosphatase Cdc25 controls cell cycle transitions by dephosphorylating CDK substrates. Here, the authors show that the Cdc25A isoform regulates glycolysis through dephosphorylation of pyruvate kinase PKM2, resulting in β-catenin activation and consequent upregulation of the transcription of glycolytic genes.
- Ji Liang
- , Ruixiu Cao
- & Zhimin Lu
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| Open AccessThe anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
Tumour hypoxia reduces the efficacy of radiotherapy. Starting from a drug screen, here the authors demonstrate that the anti-malarial, atovaquone, reduces the oxygen consumption rate of cancer cells by inhibition of mitochondrial complex III and sensitises to radiotherapy by reducing tumour hypoxia.
- Thomas M. Ashton
- , Emmanouil Fokas
- & William Gillies McKenna
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Article
| Open AccessMYC-induced reprogramming of glutamine catabolism supports optimal virus replication
Viruses can reprogram glutamine metabolism of host cells to support bioenergetics demands of viral replication. Here the authors show that adenoviral infection leads to enhanced glutamine metabolism through virus-mediated activation of MYC, which is required for optimal progeny virion generation.
- Minh Thai
- , Shivani K. Thaker
- & Heather R. Christofk
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Article
| Open AccessO-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth
The pentose phosphate pathway is aberrantly activated in cancer cells but the mechanism is unclear. Here, the authors show that G6PD, the rate-limiting enzyme in the pathway, is post-translationally modified with a sugar moiety under hypoxic conditions leading to increased production of precursors for macromolecular synthesis and antioxidants.
- Xiongjian Rao
- , Xiaotao Duan
- & Wen Yi
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Article
| Open AccessPARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation
Tumour cells can survive by evading cell death pathways and altering their metabolism to adapt to their local environment. In this study, Iansanteet al. show that the anti-apoptotic protein PARP14 maintains low PKM2 activity, leading to enhanced glycolysis, demonstrating a link between suppression of apoptosis and altered metabolism.
- Valeria Iansante
- , Pui Man Choy
- & Salvatore Papa
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The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming
The transcription factor c-Myc is a master regulator of cellular metabolism and has an important role in tumorigenesis. Phanet al. show that 14-3-3σ, an inhibitor of cell cycle progression, also suppresses tumour-promoting metabolic programmes by promoting the degradation of c-Myc.
- Liem Phan
- , Ping-Chieh Chou
- & Mong-Hong Lee
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Article |
Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1
The RNA-binding proteins Lin28A and Lin28B are known to have key roles in a variety of pathological states including cancer, obesity and diabetes. Here the authors show that Lin28A and -B alter cancer metabolism through let-7-mediated upregulation of pyruvate dehydrogenase kinase 1.
- Xiaoyu Ma
- , Chenchen Li
- & Huafeng Zhang
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Article
| Open AccessA DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect
Defective proteins or functional proteins that are no longer needed can be degraded in the endoplasmic reticulum. In this study, Lopez-Serra et al.show that DERL3, which is involved in protein degradation in the endoplasmic reticulum, is aberrantly silenced in cancer, leading to activation of a glucose transporter and dysregulated glycolysis.
- Paula Lopez-Serra
- , Miguel Marcilla
- & Manel Esteller
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Article
| Open AccessReduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway
Haem oxygenase 1 produces carbon monoxide and this byproduct is known to alter cellular signalling. Here, the authors show that carbon monoxide alters the methylation of PFKFB3 in cancer cells resulting in deregulated cellular metabolism and the shunting of glucose into the pentose phosphate pathway.
- Takehiro Yamamoto
- , Naoharu Takano
- & Makoto Suematsu
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Article
| Open AccessInduction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments
Quiescent sub-populations of cells in tumours are resistant to traditional chemotherapeutics and are responsible for tumour recurrence. Here, Zhang et al. identify a compound that kills quiescent tumour cells in solid tumour tissue by inducing mitochondrial dysfunction.
- Xiaonan Zhang
- , Mårten Fryknäs
- & Stig Linder
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Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer
Cellular metabolism is dysregulated in cancer and may be reflected in differences in the expression of metabolic genes. In this study, the authors find that mitochondrial folate-coupled dehydrogenase is increased in expression in a wide variety of cancers and negatively correlates with breast cancer patient survival.
- Roland Nilsson
- , Mohit Jain
- & Vamsi K. Mootha
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Tumour-associated mutant p53 drives the Warburg effect
Many cancers harbour mutations in the tumour suppressor p53, which often then gains oncogenic functions. Here, the authors show that mutant p53 enhances glycolysis in tumour cells by promoting glucose uptake via a mechanism involving GLUT1, RhoA and ROCK.
- Cen Zhang
- , Juan Liu
- & Zhaohui Feng
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Article |
Non-invasive in vivo assessment of IDH1 mutational status in glioma
The metabolic reaction catalysed by the isocitrate dehydrogenase 1 (IDH1) enzyme is commonly perturbed in some glioma subtypes due to gain-of-function mutations in the IDH1 gene. Here, Chaumeil et al.present a method that detects mutant IDH1 activity by measuring the levels of different hyperpolarized metabolites produced by wild-type and mutant IDH1.
- Myriam M. Chaumeil
- , Peder E. Z. Larson
- & Sabrina M. Ronen
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Article |
Landscape of the mitochondrial Hsp90 metabolome in tumours
Tumour cells utilize a pool of the molecular chaperone heat shock protein 90 to ensure correct protein folding in mitochondria. Here, the authors demonstrate that mitochondrial heat shock protein 90 regulates the folding of a subunit of the electron transport chain and that this can contribute to tumorigenesis.
- Young Chan Chae
- , Alessia Angelin
- & Dario C. Altieri
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Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation
Tumour cells may undergo a dramatic metabolic shift in which glycolysis is favoured despite the presence of oxygen. By solving its crystal structure, Hitosugi et al. reveal how phosphorylation of the enzyme phosphoglycerate mutase 1 regulates glycolytic flux in cancer cells.
- Taro Hitosugi
- , Lu Zhou
- & Jing Chen