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Lactate AND HIF-1

Hyoung Sook Park, Ji Hye Kim, Bo Kyung Sun, Sun U Song, Wonhee Suh, Jong-Hyuk Sung
It has previously been demonstrated that hypoxia has diverse stimulatory effects on adipose‑derived stem cells (ASCs), however, metabolic responses under hypoxia remain to be elucidated. Thus, the present study aimed to investigate the glucose uptake and metabolism of ASCs under hypoxic conditions, and to identify the underlying molecular mechanisms. ASCs were cultured in 1% oxygen, and experiments were conducted in vitro. As determined by proteomic analysis and western blotting, GAPDH and enolase 1 (ENO1) expression were upregulated under hypoxia...
October 5, 2016: Molecular Medicine Reports
Raymond H de Wit, Azra Mujić-Delić, Jeffrey R van Senten, Alberto Fraile-Ramos, Marco Siderius, Martine J Smit
The human cytomegalovirus (HCMV) encoded chemokine receptor US28 promotes tumorigenesis through activation of various proliferative and angiogenic signaling pathways. Upon infection, US28 displays constitutive activity and signals in a G protein-dependent manner, hijacking the host's cellular machinery. In tumor cells, the hypoxia inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis plays an important role by supporting proliferation, angiogenesis and reprogramming of energy metabolism. In this study we show that US28 signaling results in activation of the HIF-1α/PKM2 feedforward loop in fibroblasts and glioblastoma cells...
September 1, 2016: Oncotarget
Shuyong Wei, Jie Tong, Qiang Xue, Yang Liu, Xiaoyu Xu
This present paper focus on transcriptome changes of astrocytes before and after oxygen glucose deprivation (OGD) injury. Cortical astrocytes of Sprague-Dawley (SD) rats were cultured in OGD condition for 6 h, and the damage of cells was analyzed by cell's activity detection, lactate dehydrogenase leakage rate detection, annexin V-FITC (fluorescein isothiocyanate)/PI (propidium iodide) apoptosis detection, and transcriptome change detection through Affymetrix GeneChip Rat Genome 230 2.0 Array; some regulated genes were detected by quantitative real-time polymerase chain reaction (qPCR)...
September 6, 2016: Journal of Molecular Neuroscience: MN
Daniel Abebayehu, Andrew J Spence, Amina Abdul Qayum, Marcela T Taruselli, Jamie J A McLeod, Heather L Caslin, Alena P Chumanevich, Elizabeth Motunrayo Kolawole, Anuya Paranjape, Bianca Baker, Victor S Ndaw, Brian O Barnstein, Carole A Oskeritzian, Scott A Sell, John J Ryan
Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. Although IL-33 is a potent mast cell activator, how LA affects IL-33-mediated mast cell function is unknown. To investigate this, mouse bone marrow-derived mast cells were cultured with or without LA and activated with IL-33. LA reduced IL-33-mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1- and pH-dependent...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Piyushi Gupta, Ankita Singh, Pruthvi Gowda, Sadashib Ghosh, Arpita Chatterjee, Ellora Sen
Tumor infiltrating monocytes play a crucial role in tumor immune surveillance. As lactate is an important component of the tumor milieu, we investigated its role in the transcriptional regulation of MHC I which is crucial for mounting effective immune responses against tumors. Lactate elevated MHC class I expression in monocytes. Increase in HLAB expression was concomitant with increase in HIF-1α and decrease in PRMT1 levels. Interestingly, a reciprocal relationship was observed between PRMT1 and HIF-1α. While HIF-1α inhibition decreased lactate induced MHC I, both pharmacological inhibition and siRNA mediated knockdown of PRMT1 upregulated HLAB levels...
October 1, 2016: Experimental Cell Research
Sergiy M Nadtochiy, Xenia Schafer, Dragony Fu, Keith Nehrke, Joshua Munger, Paul S Brookes
2-Hydroxyglutarate (2-HG) is an important epigenetic regulator, with potential roles in cancer and stem cell biology. The d-(R)-enantiomer (d-2-HG) is an oncometabolite generated from α-ketoglutarate (α-KG) by mutant isocitrate dehydrogenase, whereas l-(S)-2-HG is generated by lactate dehydrogenase and malate dehydrogenase in response to hypoxia. Because acidic pH is a common feature of hypoxia, as well as tumor and stem cell microenvironments, we hypothesized that pH may regulate cellular 2-HG levels. Herein we report that cytosolic acidification under normoxia moderately elevated 2-HG in cells, and boosting endogenous substrate α-KG levels further stimulated this elevation...
September 16, 2016: Journal of Biological Chemistry
Ga Young Lee, Yang-Sook Chun, Hyun-Woo Shin, Jong-Wan Park
Metabolic reprogramming toward aerobic glycolysis and lactate fermentation supplies cancer cells with intermediate metabolites, which are used as macromolecule precursors. The oncogene MYC contributes to such aerobic metabolism by activating the expression of numerous genes essential for glycolysis and mitochondrial biogenesis. However, to survive and evolve in a hypoxic tumor milieu, cancer cells must revise MYC-driven metabolism because the mitochondrial respiratory chain provides free electrons to generate oxygen free radicals with inefficient production of ATP due to oxygen depletion...
July 18, 2016: Oncotarget
Marius G Bredell, Jutta Ernst, Ilhem El-Kochairi, Yuliya Dahlem, Kristian Ikenberg, Desiree M Schumann
Head and Neck cancer (HNC) is a complex mix of cancers and one of the more common cancers with a relatively poor prognosis. One of the factors that may assist us in predicting survival and allow us to adjust our treatment strategies is the presence of tumor hypoxia. In this overview we aim to evaluate the current evidence and potential clinical relevance of tumor hypoxia in head and neck cancer according to an extensive search of current literature.An abundance of evidence and often contradictory evidence is found in the literature...
May 21, 2016: Oncotarget
Mary Slingo, Mark Cole, Carolyn Carr, Mary K Curtis, Michael Dodd, Lucia Giles, Lisa C Heather, Damian Tyler, Kieran Clarke, Peter A Robbins
Hypoxia-inducible factor (HIF) appears to function as a global master regulator of cellular and systemic responses to hypoxia. HIF pathway manipulation is of therapeutic interest; however, global systemic upregulation of HIF may have as yet unknown effects on multiple processes. We used a mouse model of Chuvash polycythemia (CP), a rare genetic disorder that modestly increases expression of HIF target genes in normoxia, to understand what these effects might be within the heart. An integrated in and ex vivo approach was employed...
September 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Vicky J Young, Syed F Ahmad, Jeremy K Brown, W Colin Duncan, Andrew W Horne
STUDY QUESTION: Is inhibitor of DNA-binding protein 2 (ID2) a mediator of the transforming growth factor (TGF)-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis? SUMMARY ANSWER: The TGF-β1-induced changes in the metabolic phenotype of peritoneal mesothelial cells from women with endometriosis are mediated through the ID2 pathway. WHAT IS KNOWN ALREADY: TGF-β1 induces the metabolic conversion of glucose to lactate via aerobic glycolysis (the 'Warburg effect') in the peritoneum of women with endometriosis, through increased expression of the transcription factor hypoxia inducible factor α (HIF-1α)...
September 2016: Molecular Human Reproduction
Chun-Bo Zhao, Lei Shi, Hai-Hong Pu, Qing-Yuan Zhang
We aimed to investigate the influence of radiation on hypoxia-treated breast cancers cells and its underlying mechanism. We mimicked the hypoxic response in MCF-7 cells by the treatment of CoCl2. Meanwhile, hypoxic MCF-7 cells induced by CoCl2 or untreated MCF-7 cells were treated with or without radiation, and then treated with or without hypoxia inducible factors-1α (HIF-1α) inhibitor. Subsequently, glucose update and lactate release rate were determined by commercial kits, as well as the expressions of HIF-1α and the glucose metabolic pathway related genes, including fructose biphoshatase 1 (FBP1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase 2 (HK2), and isocitrate dehydrogenase 2 (IDH20) were detected by western blotting and/or RT-PCR...
June 24, 2016: Pathology Oncology Research: POR
Fei Luo, Xinlu Liu, Min Ling, Lu Lu, Le Shi, Xiaolin Lu, Jun Li, Aihua Zhang, Qizhan Liu
Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite, a well-established human carcinogen, is unknown. Long non-coding RNAs (lncRNAs) act as regulators in various cancers, but how lncRNAs regulate glucose metabolism remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases lactate production; glucose consumption; and expression of glycolysis-related genes, including HK-2, Eno-1, and Glut-4...
September 2016: Biochimica et Biophysica Acta
Ling Zeng, Hai-Yun Zhou, Na-Na Tang, Wei-Feng Zhang, Gui-Jun He, Bo Hao, Ya-Dong Feng, Hong Zhu
AIM: To investigate the influence of phosphatidylinositol-3-kinase protein kinase B (PI3K/AKT)-HIF-1α signaling pathway on glycolysis in esophageal carcinoma cells under hypoxia. METHODS: Esophageal carcinoma cell lines Eca109 and TE13 were cultured under hypoxia environment, and the protein, mRNA and activity levels of hypoxia inducible factor-1 alpha (HIF-1α), glucose transporter 1, hexokinase-II, phosphofructokinase 2 and lactate dehydrogenase-A were determined...
May 28, 2016: World Journal of Gastroenterology: WJG
Chen-Sung Lin, Hui-Ting Lee, Ming-Huei Lee, Siao-Cian Pan, Chen-Yeh Ke, Allen Wen-Hsiang Chiu, Yau-Huei Wei
We investigated the role of mitochondrial DNA (mtDNA) copy number alteration in human renal cell carcinoma (RCC). The mtDNA copy numbers of paired cancer and non-cancer parts from five resected RCC kidneys after radical nephrectomy were determined by quantitative polymerase chain reaction (Q-PCR). An RCC cell line, 786-O, was infected by lentiviral particles to knock down mitochondrial transcriptional factor A (TFAM). Null target (NT) and TFAM-knockdown (TFAM-KD) represented the control and knockdown 786-O clones, respectively...
2016: International Journal of Molecular Sciences
Koji Harada, Tarannum Ferdous, Toyoko Harada, Yoshiya Ueyama
Cancer cells show enhanced glucose consumption and lactate production even in the presence of abundant oxygen, a phenomenon known as the Warburg effect, which is related to tumor proliferation, progression and drug-resistance in cancers. Hypoxia-inducible factor-1 (HIF-1) and several members of Phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway positively contribute to the Warburg effect, whereas AMP activated protein Kinase (AMPK) acts as a negative regulator...
July 2016: International Journal of Oncology
Kelei Dong, Hua Ni, Meiling Wu, Ziqing Tang, Michael Halim, Dongyun Shi
Oxidative stress is known to contribute to insulin resistance in diabetes, however the mechanism is not clear. Here we show that reactive oxygen species (ROS) could reprogram the glucose metabolism through upregulating the pentose pathway so as to induce insulin resistance in type 2 diabetes (T2DM). By using streptozotocin-high fat diet (STZ-HFD) induced T2DM in rats, we show that diabetic rats exhibited high level of oxidative stress accompanied with insulin resistance. Hypoxia inducible factor (HIF-1α) protein expression as well as its downstream target glucokinase (GK), were upregulated; The glycogen synthesis increased accordingly; However the glycolysis was inhibited as indicated by decreased phosphofructokinase-1 (PFK-1), pyruvate kinase (PK), phospho-PFK-2/PFK-2 (p-PFK-2/PFK-2) ratio, lactate dehydrogenase (LDH) and pyruvate dehydrogenase kinase (PDK); Pyruvate dehydrogenase (PDH) which promotes pyruvate to generate acetyl-CoA declined as well...
August 5, 2016: Biochemical and Biophysical Research Communications
Yik Lung Chan, Sonia Saad, Carol Pollock, Brian Oliver, Ibrahim Al-Odat, Amgad A Zaky, Nicole Jones, Hui Chen
Maternal cigarette smoke exposure (SE) during gestation can cause lifelong adverse effects in the offspring's brain. Several factors may contribute including inflammation, oxidative stress and hypoxia, whose changes in the developing brain are unknown. Female Balb/c mice were exposed to cigarette smoke prior to mating, during gestation and lactation. Male offspring were studied at postnatal day (P) 1, P20 and 13 weeks (W13). SE dams had reduced inflammatory mediators (IL-1β, IL-6 and toll like receptor (TLR)4 mRNA), antioxidant (manganese superoxide dismutase (MnSOD)), and increased mitochondrial activities (OXPHOS-I, III and V) and protein damage marker nitrotyrosine...
2016: Scientific Reports
L Liu, Y Wang, R Bai, K Yang, Z Tian
Deregulation of microRNAs in human malignancies has been well documented, among which microRNA-186 (miR-186) has an antiproliferative role in some carcinomas. Here we demonstrate that low expression of miR-186 facilitates aerobic glycolysis in gastric cancer. MiR-186 suppresses cell proliferation induced by hypoxia inducible factor 1 alpha (HIF-1α) in gastric cancer cell lines MKN45 and SGC7901. Cellular glycolysis, including cellular glucose uptake, lactate, ATP/ADP and NAD+/NADH ratios, are also inhibited by miR-186...
2016: Oncogenesis
Devin P Devor, Donald E Kuhn, Kristin M O'Brien, Elizabeth L Crockett
Understanding what limits the capacity of organisms to tolerate increasing temperatures is a critical objective in comparative biology. Using an experimental system of Antarctic notothenioid fishes, we sought to determine whether a mismatch between oxygen demand and oxygen supply was responsible for setting thermal tolerance limits. Previous studies have shown that Antarctic icefishes (family Channichthyidae), which lack hemoglobin, have lower critical thermal maxima (CTmax) than red-blooded notothenioids collected from the same region of the Antarctic (Western Antarctic Peninsula)...
January 2016: Physiological and Biochemical Zoology: PBZ
Keni Cota-Ruiz, Lilia Leyva-Carrillo, Alma B Peregrino-Uriarte, Elisa M Valenzuela-Soto, Teresa Gollas-Galván, Silvia Gómez-Jiménez, Jesús Hernández, Gloria Yepiz-Plascencia
HIF-1 is a transcription factor that controls a widespread range of genes in metazoan organisms in response to hypoxia and is composed of α and β subunits. In shrimp, phosphofructokinase (PFK) and fructose bisphosphatase (FBP) are up-regulated in hypoxia. We hypothesized that HIF-1 is involved in the regulation of PFK and FBP genes in shrimp hepatopancreas under hypoxia. Long double stranded RNA (dsRNA) intramuscular injection was utilized to silence simultaneously both HIF-1 subunits, and then, we measured the relative expression of PFK and FBP, as well as their corresponding enzymatic activities in hypoxic shrimp hepatopancreas...
August 2016: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
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