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Warburg effect

Ling Li, Yingchun Liang, Lei Kang, Yang Liu, Shan Gao, Siyu Chen, Ying Li, Wenye You, Qian Dong, Tian Hong, Zhifeng Yan, Shuai Jin, Tao Wang, Wei Zhao, Haixing Mai, Jun Huang, Xiao Han, Quanbo Ji, Qi Song, Chao Yang, Shixin Zhao, Xiaojie Xu, Qinong Ye
Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth...
February 8, 2018: Cancer Cell
Po-Lin Tseng, Wei-Hsuan Wu, Tsung-Hui Hu, Chih-Wei Chen, Hung-Chi Cheng, Chien-Feng Li, Wen-Hui Tsai, Hui-Ju Tsai, Meng-Che Hsieh, Jiin-Haur Chuang, Wen-Tsan Chang
Changes in TCA cycle enzymes or respiratory activity are possible mechanisms of aerobic glycolysis that contributes to tumor progression. To clarify whether the decrease of succinate dehydrogenase B (SDHB) alters energy metabolism, induces the Warburg effect and results in tumor malignancy, SDHB expression was examined and modulated in hepatocellular carcinoma (HCC) tissues and cells, respectively. SDHB level was often decreased in malignant HCC cells and tissues. Furthermore, the reduced SDHB expression was associated with advanced tumor stage and poor survival rate...
February 15, 2018: Scientific Reports
Sahithi Pamarthy, Arpita Kulshrestha, Gajendra K Katara, Kenneth D Beaman
The Vacuolar ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. The structure of V-ATPase has been highly conserved among all eukaryotic cells and is involved in diverse functions across species. V-ATPase is best known for its acidification of endosomes and lysosomes and is also important for luminal acidification of specialized cells. Several reports have suggested the involvement of V-ATPase in maintaining an alkaline intracellular and acidic extracellular pH thereby aiding in proliferation and metastasis of cancer cells respectively...
February 15, 2018: Molecular Cancer
Katie J Sikes, Jun Li, Shu-Guang Gao, Quan Shen, John D Sandy, Anna Plaas, Vincent M Wang
Healthy tendons are maintained in homeostasis through controlled usage of glucose for energy and redox equilibrium. Tendon cell stress imposed by overuse injury or vascular insufficiency is accompanied by activation of wound healing pathways which facilitate an adaptive response and the restoration of homeostasis. To understand this response at the gene expression level we have studied the in vivo effects of injected TGF-β1 in a murine model of tendinopathy, as well as treatment of murine tendon explants with either TGF-β1 or hypoxia in vitro...
February 15, 2018: Connective Tissue Research
Jihong Sun, Jingjing Li, Zhixian Guo, Lu Sun, Chenghui Juan, Yubing Zhou, Hongli Gu, Yan Yu, Qiuyue Hu, Quancheng' Kan, Zujiang Yu
Most cancers rely disproportionately on glycolysis for energy even in the presence of adequate oxygen supply, a condition known as "aerobic glycolysis", or the "Warburg effect". Pyruvate dehydrogenase E1a subunit (PDHA1) is one of main factors for metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and has been suggested to be closely associated with tumorigenesis. Here we observed that PDHA1 protein was reduced in hepatocellular carcinoma (HCC) specimens by immunohistochemistry and western blot, which was significantly associated with poor overall survival...
February 14, 2018: Oncology Research
Ryo Yonashiro, Kayoko Eguchi, Masaki Wake, Norihiko Takeda, Koh Nakayama
Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable since it relies on PDH kinases which are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1β subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia...
February 7, 2018: Cancer Research
Roberto Serna-Blasco, Marta Sanz-Álvarez, Óscar Aguilera, Jesús García-Foncillas
RAS protein family members (KRAS4A, KRAS4B, HRAS and NRAS) function as GDP-GTP-regulated on-off switches, which regulate cytoplasmic-nuclear signaling networks ruling diverse normal cellular processes. Constitutive activating mutations in RAS genes are found in up to 30% of human cancers, and remarkably, the oncogenic Ras mutations and mutations in other components of Ras/MAPK signaling pathways seem to be mutually exclusive in most tumors, pointing out that deregulation of Ras-dependent signaling is an essential requirement for tumorigenesis...
February 9, 2018: Seminars in Cancer Biology
Naomi Dirckx, Robert J Tower, Evi M Mercken, Roman Vangoitsenhoven, Caroline Moreau-Triby, Tom Breugelmans, Elena Nefyodova, Ruben Cardoen, Chantal Mathieu, Bart Van der Schueren, Cyrille B Confavreux, Thomas L Clemens, Christa Maes
The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel-Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin...
February 12, 2018: Journal of Clinical Investigation
Ching-Wen Chang, Yu-Syuan Chen, Yeou-Guang Tsay, Chia-Li Han, Yu-Ju Chen, Cheng-Chieh Yang, Kai-Feng Hung, Chao-Hsiung Lin, Tsung-Yen Huang, Shou-Yen Kao, Te-Chang Lee, Jeng-Fan Lo
Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we have identified that cancer cells containing low intracellular reactive oxygen species levels (ROSLow cells) display enhanced features of CICs. However, the specific metabolic signatures of CICs remain unclear and are required for further characterization by systemic screenings. Herein, we first showed CICs mainly relying on glycolysis that was important for the maintenance of stemness properties...
February 7, 2018: Cell Death & Disease
Philip Möller, Xiaochen Liu, Stefan Schuster, Daniel Boley
Many differentiated cells rely primarily on mitochondrial oxidative phosphorylation for generating energy in the form of ATP needed for cellular metabolism. In contrast most tumor cells instead rely on aerobic glycolysis leading to lactate to about the same extent as on respiration. Warburg found that cancer cells to support oxidative phosphorylation, tend to ferment glucose or other energy source into lactate even in the presence of sufficient oxygen, which is an inefficient way to generate ATP. This effect also occurs in striated muscle cells, activated lymphocytes and microglia, endothelial cells and several mammalian cell types, a phenomenon termed the "Warburg effect"...
2018: PloS One
Bethany R Mordhorst, Stephanie L Murphy, Rence M Ross, Melissa S Samuel, Shirley Rojas Salazar, Tieming Ji, Susanta K Behura, Kevin D Wells, Jonathan A Green, Randall S Prather
The Warburg effect is a metabolic phenomenon characterized by increased glycolytic activity, decreased mitochondrial oxidative phosphorylation, and the production of lactate. This metabolic phenotype is characterized in rapidly proliferative cell types such as cancerous cells and embryonic stem cells. We hypothesized that a Warburg-like metabolism could be achieved in other cell types by treatment with pharmacological agents, which might, in turn, facilitate nuclear reprogramming. The aim of this study was to treat fibroblasts with CPI-613 and PS48 to induce a Warburg-like metabolic state...
February 2018: Cellular Reprogramming
Thibaut Girardot, Thomas Rimmelé, Guillaume Monneret, Julien Textoris, Fabienne Venet
BACKGROUND: Sepsis-associated hyperlactatemia is a widely used biomarker, associated with initial severity and poor outcomes. This increased circulating lactate concentration has been proposed to result in part from a mismatch between oxygen delivery and demand in organs. However, other mechanisms may participate. In particular, a metabolic reprogramming similar to the Warburg effect initially described in cancer cells could lead to increased lactate production by immune cells such as T lymphocytes after sepsis...
February 5, 2018: Intensive Care Medicine Experimental
Misa Yokoyama, Nobuhiro Tanuma, Rie Shibuya, Takeharu Shiroki, Makoto Abue, Kuniharu Yamamoto, Koh Miura, Kazunori Yamaguchi, Ikuro Sato, Keiichi Tamai, Kennichi Satoh
The majority of cancer cells maintain a high glycolytic activity and an increased lactate production, even in a well oxygenated environment. This phenomenon is known as the Warburg effect. Previous studies have revealed that various types of cancer selectively express the pyruvate kinase M2 isoform (PKM2), and that PKM2 plays a pivotal role in the Warburg effect. Although elevated PKM2 levels have been observed in pancreatic cancer and other types of cancer, little is known about the biological function of PKM2...
January 30, 2018: International Journal of Oncology
B R Mordhorst, S L Murphy, R M Ross, J A Benne, M S Samuel, R F Cecil, B K Redel, L D Spate, C N Murphy, K D Wells, J A Green, R S Prather
Somatic cell nuclear transfer is a valuable technique for the generation of genetically engineered animals, however the efficiency of cloning in mammalian species is low (1-3%). Differentiated somatic cells commonly used in nuclear transfer utilize the tricarboxylic acid cycle and cellular respiration for energy production. Comparatively the metabolism of somatic cells contrasts that of the cells within the early embryos which predominately use glycolysis. Early embryos (prior to implantation) are evidenced to exhibit characteristics of a Warburg Effect (WE)-like metabolism...
February 2, 2018: Molecular Reproduction and Development
Rahul Jandial, Josh Neman, Punnajit P Lim, Daniel Tamae, Claudia M Kowolik, Gerald E Wuenschell, Sarah C Shuck, Alexandra K Ciminera, Luis R De Jesus, Ching Ouyang, Mike Y Chen, John Termini
Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches...
January 30, 2018: International Journal of Molecular Sciences
Shaoxun Xiang, Hao Gu, Lei Jin, Rick F Thorne, Xu Dong Zhang, Mian Wu
The oncoprotein c-Myc plays an important role in regulating glycolysis under normoxia; yet, in cancer cells, HIF1α, which is essential for driving glycolysis under hypoxia, is often up-regulated even in the presence of oxygen. The relationship between these two major regulators of the Warburg effect remains to be fully defined. Here we demonstrate that regulation of a long noncoding RNA (lncRNA), named IDH1-AS1, enables c-Myc to collaborate with HIF1α in activating the Warburg effect under normoxia. c-Myc transcriptionally repressed IDH1-AS1, which, upon expression, promoted homodimerization of IDH1 and thus enhanced its enzymatic activity...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
P Aswini, R Grace Raji, K Haritha, E Lincy, V B Sameer Kumar
Cancer cells exhibit increased dependency on aerobic glycolysis, a phenomenon referred as the 'Warburg effect' and therefore, blocking glycolysis by using non-metabolizable analogues of glucose, like 2-Deoxy glucose (2-DG), has been proposed to be of huge therapeutic importance. One of the major drawbacks of using 2-DG as a chemotherapeutic agent is that it can induce ER stress. ER stress is a hall mark in many solid tumors and the unfolded protein response (UPR) associated with it initiates many survival mechanisms in cancer cells...
January 29, 2018: Journal of Cellular Biochemistry
Zhendong Liu, Liang Li, Bei Xue
Ganoderic acid D (GAD) is a highly oxygenated tetracyclic triterpenoid. This study aims to assess the effects of GAD on the energy metabolism of colon cancer through the regulation of SIRT3 expression and whether this effect is related to acetylated cyclophilin D. The results demonstrated that GAD inhibits the energy reprogramming of colon cancer cells including glucose uptake, lactate production, pyruvate and acetyl-coenzyme production in colon cancer cells. Meanwhile, GAD upregulated the protein expression of SIRT3...
January 24, 2018: European Journal of Pharmacology
S Santasusagna, I Moreno, A Navarro, C Muñoz, F Martinez, R Hernández, J J Castellano, M Monzo
PURPOSE: Increasing evidence shows that altered metabolism is a critical hallmark in colon cancer. There is a strong need to explore the molecular mechanisms underlying cancer metabolism. Whether the aberrant expression of microRNAs contributes to cancer metabolism is not fully understood. miR-328 is a putative potential target of SLC2A1, but the regulating mechanism between them remains unknown. We have examined whether miR-328 directly regulates SLC2A1/GLUT1 expression in colon cancer cells...
January 26, 2018: Clinical & Translational Oncology
Xiang Li, Shichang Deng, Mingliang Liu, Yan Jin, Shuai Zhu, Shijiang Deng, Jingyuan Chen, Chi He, Qi Qin, Chunyou Wang, Gang Zhao
Cancer cells predominantly produce energy at a high rate of glycolysis even in aerobic environment. It is termed as Warburg effect and is necessary for the tumorigenesis. Studies showed pyruvate kinase M2 (PKM2), a key regulator of the Warburg effect, is overexpressed and involved in numerous cancers. However, the expression and function of PKM2 in pancreatic cancer (PC) remain undefined. Our results showed that PKM2 is overexpressed in the PC tissue compared to the peritumoral tissue. Unexpected, the downregulation of PKM2 did not affect the proliferation, invasion, and chemoresistance of PC cells...
January 26, 2018: Cell Death & Disease
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