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Aerobic glycolysis

Kaichun Li, Mingzhen Ying, Dan Feng, Jie Du, Shiyu Chen, Bing Dan, Cuihua Wang, Yajie Wang
Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme in gluconeogenesis, is a tumor suppressor that frequently down-regulated in cancers, especially breast cancer. Here, we provide both supporting and contradicting evidences about the expression pattern and function of FBP1 in breast cancer. Data mining of Oncomine database showed that FBP1 is commonly up-regulated in tumor tissues compared with non-tumor tissues regardless of histological type. Analysis of a large-scale cohort derived from Kaplan-Meier Plotter showed that lower FBP1 expression associated with poor clinical outcome...
October 22, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Min Xie, Yan Yu, Rui Kang, Shan Zhu, Liangchun Yang, Ling Zeng, Xiaofang Sun, Minghua Yang, Timothy R Billiar, Haichao Wang, Lizhi Cao, Jianxin Jiang, Daolin Tang
Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages...
October 25, 2016: Nature Communications
Margaret O James, Stephan C Jahn, Guo Zhong, Marci G Smeltz, Zhiwei Hu, Peter W Stacpoole
Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen...
October 19, 2016: Pharmacology & Therapeutics
Ruinan Gu, Fali Zhang, Gang Chen, Chaojun Han, Jay Liu, Zhaoxiang Ren, Yi Zhu, John L Waddington, Long Tai Zheng, Xuechu Zhen
Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1α and ROS/HIF-1α signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis...
October 18, 2016: Brain, Behavior, and Immunity
Siroon Bekkering, Inge van den Munckhof, Tim Nielen, Evert Lamfers, Charles Dinarello, Joost Rutten, Jacqueline de Graaf, Leo A B Joosten, Mihai G Netea, Marc E R Gomes, Niels P Riksen
BACKGROUND AND AIMS: We have recently reported that monocytes can undergo functional and transcriptional reprogramming towards a long-term pro-inflammatory phenotype after brief in vitro exposure to atherogenic stimuli such as oxidized LDL. This process is termed 'trained immunity', and is mediated by epigenetic remodeling and a metabolic switch towards increased aerobic glycolysis. We hypothesize that trained immunity contributes to atherogenesis. Therefore, we investigated the inflammatory phenotype and epigenetic remodeling of monocytes from patients with and without established atherosclerosis...
October 12, 2016: Atherosclerosis
Justus Mahnke, Valéa Schumacher, Stefanie Ahrens, Nadja Käding, Lea Marie Feldhoff, Magdalena Huber, Jan Rupp, Friederike Raczkowski, Hans-Willi Mittrücker
The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for TH2 and TH17 cell formation and controls peripheral CD8(+) T cell differentiation. We used Listeria monocytogenes infection to characterize the function of IRF4 in TH1 responses. IRF4(-/-) mice generated only marginal numbers of listeria-specific TH1 cells. After transfer into infected mice, IRF4(-/-) CD4(+) T cells failed to differentiate into TH1 cells as indicated by reduced T-bet and IFN-γ expression, and showed limited proliferation...
October 20, 2016: Scientific Reports
Alberto L Horenstein, Valeria Quarona, Denise Toscani, Federica Costa, Antonella Chillemi, Vito Pistoia, Nicola Giuliani, Fabio Malavasi
Human myeloma cells express CD38 at high levels and grow in hypoxic niches inside the bone marrow. Myeloma cells respond to hypoxia with metabolic changes leading to aerobic glycolysis, thus reducing ATP and increasing NAD(+). Our hypothesis is that these conditions favor the enzymatic pathways involved in the production of adenosine in the niche. Within the niche, NAD(+) is able to activate a discontinuous adenosinergic pathway that relies upon CD38, CD203a, and CD73 or TRACP, according to the environmental pH...
October 13, 2016: Molecular Medicine
Marie-Julie Nokin, Florence Durieux, Paul Peixoto, Barbara Chiavarina, Olivier Peulen, Arnaud Blomme, Andrei Turtoi, Brunella Costanza, Nicolas Smargiasso, Dominique Baiwir, Jean L Scheijen, Casper G Schalkwijk, Justine Leenders, Pascal De Tullio, Elettra Bianchi, Marc Thiry, Koji Uchida, David A Spiegel, James R Cochrane, Craig A Hutton, Edwin De Pauw, Philippe Delvenne, Dominique Belpomme, Vincent Castronovo, Akeila Bellahcène
Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion...
October 19, 2016: ELife
Tatjana Harting, Mandy Stubbendorff, Saskia Willenbrock, Siegfried Wagner, Patrik Schadzek, Anaclet Ngezahayo, Hugo Murua Escobar, Ingo Nolte
The Warburg effect describes the ability of cancer cells to produce energy via aerobic glycolysis instead of oxidative phosphorylation of pyruvate. This deviation in mitochondrial metabolism inhibits apoptosis, allowing increased proliferation under conditions of reduced oxygen levels. Dichloroacetate (DCA) was successfully used in several human cancer cell lines to reactivate oxidative phosphorylation in mitochondria. The aim of this study was the characterization and response of canine cancer cell lines after DCA exposure...
October 5, 2016: International Journal of Oncology
Ivana Jochmanova, Karel Pacak
Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads to a switch from oxidative phosphorylation to aerobic glycolysis. This metabolic shift results in activation of numerous signaling and metabolic pathways supporting cell proliferation and survival. Recent progress in genetics and metabolomics has allowed us to take a closer look at the metabolic changes present in pheochromocytomas (PHEO) and paragangliomas (PGL)...
October 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Baijun Dong, Yujing Gao, Xunlei Kang, Hongchang Gao, Jin Zhang, Hua Guo, Mingjian J You, Wei Xue, Jinke Cheng, Yiran Huang
Metabolic shift toward aerobic glycolysis is a fundamental element contributing to the development and progression of clear cell renal cell carcinoma (ccRCC). We and others previously observed enhanced glycolysis and diminished tricarboxylic acid (TCA) cycle activity in ccRCC tissue. Here, by integrated gene expression and metabolomic analyses of 36 matched pairs of tumor and adjacent normal tissues, we showed that expression of Sentrin/SUMO-specific protease 1 (SENP1) is positively associated with glycolysis levels in ccRCC...
October 12, 2016: Oncotarget
Jingtao Luo, Yun Hong, Xiaoan Tao, Xi Wei, Lun Zhang, Qiang Li
Unlike normal cells, cancer cells are recently identified to rely on aerobic glycolysis for energy production called the Warburg effect. Several attempts are being made to target this metabolic reprogramming pathway in treating cancers; however, the successful rate is very limited. In this study, we investigated the functional roles of fatty acid oxidation key enzyme carnitine palmitoyl transferase 1a (CPT-1a), during the metabolic programming of pancreatic ductal adenocarcinoma (PDAC) cells induced by glucose deprivation...
October 13, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Stephanie Sprowl-Tanio, Amber N Habowski, Kira T Pate, Miriam M McQuade, Kehui Wang, Robert A Edwards, Felix Grun, Yung Lyou, Marian L Waterman
BACKGROUND: There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism. In colon cancer, this reprogramming is due to direct regulation of pyruvate dehydrogenase kinase 1 (PDK1) gene transcription. Additional metabolism genes are sensitive to Wnt signaling and exhibit correlative expression with PDK1. Whether these genes are also regulated at the transcriptional level, and therefore a part of a core metabolic gene program targeted by oncogenic WNT signaling, is not known...
2016: Cancer & Metabolism
T Yu, G Yang, Y Hou, X Tang, C Wu, X-A Wu, L Guo, Q Zhu, H Luo, Y-E Du, S Wen, L Xu, J Yin, G Tu, M Liu
Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs...
October 10, 2016: Oncogene
Min Peng, Na Yin, Sagar Chhangawala, Ke Xu, Christina S Leslie, Ming O Li
Aerobic glycolysis (the Warburg effect) is a metabolic hallmark of activated T cells, and has been implicated in augmenting effector T cell responses including expression of the proinflammatory cytokine interferon-γ (IFN-γ) via 3' untranslated region (3'UTR)-mediated mechanisms. Here, we show that lactate dehydrogenase A (LDHA) is induced in activated T cells to support aerobic glycolysis but promotes IFN-γ expression independently of its 3'UTR. Instead, LDHA maintains high levels of acetyl-coenzyme A to enhance histone acetylation and transcription of Ifng Ablation of LDHA in T cells protects mice from immunopathology triggered by excessive IFN-γ expression or deficiency of regulatory T cells...
September 29, 2016: Science
Jorgelindo da Veiga Moreira, Minoo Hamraz, Mohammad Abolhassani, Erwan Bigan, Sabine Pérès, Loïc Paulevé, Marcel Levy Nogueira, Jean-Marc Steyaert, Laurent Schwartz
To better understand the energetic status of proliferating cells, we have measured the intracellular pH (pHi) and concentrations of key metabolites, such as adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP) in normal and cancer cells, extracted from fresh human colon tissues. Cells were sorted by elutriation and segregated in different phases of the cell cycle (G0/G1/S/G2/M) in order to study their redox (NAD, NADP) and bioenergetic (ATP, pHi) status...
October 3, 2016: Metabolites
Daniela Volonte, Zhongmin Liu, Sruti Shiva, Ferruccio Galbiati
Mitochondrial proteases ensure mitochondrial integrity and function after oxidative stress by providing mitochondrial protein quality control. However, the molecular mechanisms that regulate this basic biological function in eukaryotic cells remain largely unknown. Caveolin-1 is a scaffolding protein involved in signal transduction. We find that AFG3L2, a m-AAA type of mitochondrial protease, is a novel caveolin-1-interacting protein in vitro. We show that oxidative stress promotes the translocation of both caveolin-1 and AFG3L2 to mitochondria, enhances the interaction of caveolin-1 with AFG3L2 in mitochondria and stimulates mitochondrial protease activity in wild-type fibroblasts...
October 4, 2016: Aging
Lincy Edatt, K Haritha, T V Sruthi, P Aswini, V B Sameer Kumar
MMP9 is a member of the family of zinc-containing endopeptidases which degrade various components of the extracellular matrix, thereby regulating matrix remodeling. Since matrix remodeling plays an important role during growth and progression of cancer and considering the fact that, tumor cells switch to aerobic glycolysis as its major energy source, this study was designed to analyze if partial inhibition of glycolysis (the major energy pathway during hypoxia) can be used as a means to control matrix remodeling in terms of MMP9 activity and expression...
October 4, 2016: Molecular and Cellular Biochemistry
Taro Sugiyama, Kohei Taniguchi, Nobuhisa Matsuhashi, Toshihiro Tajirika, Manabu Futamura, Tomoaki Takai, Yukihiro Akao, Kazuhiro Yoshida
The metabolism in tumor cells shifts from oxidative phosphorylation to glycolysis even in an aerobic environment, which phenomenon is known as the Warburg effect. This effect is regulated mainly by polypyrimidine tract-binding protein 1 (PTBP1), which is a splicer of the mRNA for the rate-limiting enzymes of glycolysis, pyruvate kinase muscle 1 and 2 (PKM1 and PKM2). In the present study, we demonstrated that miR-133b reduced PTBP1 expression at translational level and that the expression levels of miR-133b were significantly down-regulated in gastric cancer clinical samples and human cell lines, whereas the protein expression level of PTBP1 was up-regulated in 80% of the 20 clinical samples of gastric cancer examined...
October 3, 2016: Cancer Science
Valerie A Gerriets, Rigel J Kishton, Marc O Johnson, Sivan Cohen, Peter J Siska, Amanda G Nichols, Marc O Warmoes, Aguirre A de Cubas, Nancie J MacIver, Jason W Locasale, Laurence A Turka, Andrew D Wells, Jeffrey C Rathmell
CD4(+) effector T cells (Teff cells) and regulatory T cells (Treg cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K (phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for Teff cell proliferation and inflammatory function, the mechanisms that regulate Treg cell metabolism and function remain unclear...
October 3, 2016: Nature Immunology
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