scholarly journals Navigating oxygen deprivation: liver transcriptomic responses of the red eared slider turtle to environmental anoxia

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8144 ◽  
Author(s):  
Kyle K. Biggar ◽  
Jing Zhang ◽  
Kenneth B. Storey
Keyword(s):  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Anoxia Tolerance ◽  
Molecular Processes ◽  
Painted Turtles ◽  
Slider Turtle ◽  
Damage Repair ◽  
Transcriptomic Responses ◽  
Molecular Landscape ◽  
Transcriptomic Changes

The best facultative anaerobes among vertebrates are members of the genera Trachemys (pond slider turtles) and Chrysemys (painted turtles), and are able to survive without oxygen for up to 12 to 18 weeks at ∼3 °C. In this study, we utilized RNAseq to profile the transcriptomic changes that take place in response to 20 hrs of anoxia at 5 °C in the liver of the red eared slide turtle (Trachemys scripta elegans). Sequencing reads were obtained from at least 18,169 different genes and represented a minimum 49x coverage of the C. picta bellii exome. A total of 3,105 genes showed statistically significant changes in gene expression between the two animal groups, of which 971 also exhibited a fold change equal to or greater than 50% of control normoxic values. This study also highlights a number of anoxia-responsive molecular pathways that are may be important to navigating anoxia survival. These pathways were enriched in mRNA found to significantly increase in response to anoxia and included molecular processes such as DNA damage repair and metabolic reprogramming. For example, our results indicate that the anoxic turtle may utilize succinate metabolism to yield a molecule of GTP in addition to the two molecules that results from lactate production, and agrees with other established models of anoxia tolerance. Collectively, our analysis provides a snapshot of the molecular landscape of the anoxic turtle and may provide hints into the how this animal is capable of surviving this extreme environmental stress.

scholarly journals Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 432
Author(s):  
Iván Ponce ◽  
Nelson Garrido ◽  
Nicolás Tobar ◽  
Francisco Melo ◽  
Patricio C. Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Glucose Transporter ◽  
Lactate Production ◽  
Resonance Energy ◽  
Metabolic Reprogramming ◽  
Dependent Manner ◽  
Functional Link

Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work was to investigate the possible functional link between these two processes. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material, to which matrix molecules were covalently linked. We evaluated metabolite transport in stromal cells using two different FRET (Fluorescence Resonance Energy Transfer) nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response was correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote metabolic reprograming and also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming, and cancer malignancy.

scholarly journals Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3018
Author(s):  
Marek Samec ◽  
Alena Liskova ◽  
Lenka Koklesova ◽  
Kevin Zhai ◽  
Elizabeth Varghese ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Effective Prevention ◽  
Anti Cancer ◽  
Glucose 6 Phosphate Dehydrogenase

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

scholarly journals Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Hanyue Chang ◽  
Qiaoshi Xu ◽  
Jiayi Li ◽  
Mingyu Li ◽  
Zhiyuan Zhang ◽  
...  
Keyword(s):  
Critical Role ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Histone Deacetylase 3 ◽  
Proliferation And Metastasis ◽  
Immunosuppressive Microenvironment ◽  
Transcriptional Complex

AbstractPyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC.

scholarly journals The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5557
Author(s):  
Alexandre Vallée ◽  
Yves Lecarpentier ◽  
Jean-Noël Vallée
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Warburg Effect ◽  
Target Genes ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Pyruvate Dehydrogenase Kinase ◽  
The Warburg Effect

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

scholarly journals Mitochondrial genome and its regulator TFAM modulates head and neck tumourigenesis through intracellular metabolic reprogramming and activation of oncogenic effectors

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Yi-Ta Hsieh ◽  
Hsi-Feng Tu ◽  
Muh-Hwa Yang ◽  
Yi-Fen Chen ◽  
Xiang-Yun Lan ◽  
...  
Keyword(s):  
Head And Neck ◽  
Tongue Cancer ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Cellular Level ◽  
Metabolic Reprogramming ◽  
Transport Chain ◽  
Genetically Manipulated ◽  
The Impact

AbstractMitochondrial transcriptional factor A (TFAM) acts as a key regulatory to control mitochondrial DNA (mtDNA); the impact of TFAM and mtDNA in modulating carcinogenesis is controversial. Current study aims to define TFAM mediated regulations in head and neck cancer (HNC). Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical associations of TFAM and mtDNA encoded Electron Transport Chain (ETC) genes in regulating HNC tumourigenesis were also examined in HNC specimens. At cellular level, TFAM silencing led to an enhanced cell growth, motility and chemoresistance whereas enforced TFAM expression significantly reversed these phenotypic changes. These TFAM mediated cellular changes resulted from (1) metabolic reprogramming by directing metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater lactate production; and/or (2) enhanced ERK1/2-Akt-mTORC-S6 signalling activity in response to TFAM induced mtDNA perturbance. Clinical impacts of TFAM and mtDNA were further defined in carcinogen-induced mouse tongue cancer and clinical human HNC tissues; as the results showed that TFAM and mtDNA expression were significantly dropped in tumour compared with their normal counterparts and negatively correlated with disease progression. Collectively, our data uncovered a tumour-suppressing role of TFAM and mtDNA in determining HNC oncogenicity and potentially paved the way for development of TFAM/mtDNA based scheme for HNC diagnosis.

scholarly journals Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 813 ◽  
Author(s):  
Michelle K. Y. Siu ◽  
Yu-Xin Jiang ◽  
Jing-Jing Wang ◽  
Thomas H. Y. Leung ◽  
Chae Young Han ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Cancer Metastasis ◽  
Ovarian Cancer Cell ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Hexokinase 2 ◽  
Cell Migration And Invasion

Metabolic reprogramming is a common phenomenon in cancers. Thus, glycolytic enzymes could be exploited to selectively target cancer cells in cancer therapy. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in glucose metabolism. Here, we demonstrated that HK2 was overexpressed in ovarian cancer and displayed significantly higher expression in ascites and metastatic foci. HK2 expression was significantly associated with advanced stage and high-grade cancers, and was an independent prognostic factor. Functionally, knockdown of HK2 in ovarian cancer cell lines and ascites-derived tumor cells hindered lactate production, cell migration and invasion, and cell stemness properties, along with reduced FAK/ERK1/2 activation and metastasis- and stemness-related genes. 2-DG, a glycolysis inhibitor, retarded cell migration and invasion and reduced stemness properties. Inversely, overexpression of HK2 promoted cell migration and invasion through the FAK/ERK1/2/MMP9 pathway, and enhanced stemness properties via the FAK/ERK1/2/NANOG/SOX9 cascade. HK2 abrogation impeded in vivo tumor growth and dissemination. Notably, ovarian cancer-associated fibroblast-derived IL-6 contributed to its up-regulation. In conclusion, HK2, which is regulated by the tumor microenvironment, controls lactate production and contributes to ovarian cancer metastasis and stemness regulation via FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression. HK2 could be a potential prognostic marker and therapeutic target for ovarian cancer.

scholarly journals Over-wintering Characteristics of West-Central Wisconsin Blanding's Turtles, Emydoidea blandingii

2010 ◽  
Vol 124 (2) ◽  
pp. 134 ◽  
Author(s):  
Richard P. Thiel ◽  
Timothy T. Wilder
Keyword(s):  
Chrysemys Picta ◽  
Anoxia Tolerance ◽  
Chelydra Serpentina ◽  
Emydoidea Blandingii ◽  
Anoxic Conditions ◽  
Painted Turtles ◽  
West Central ◽  
Remarkable Degree ◽  
Snapping Turtles

Hibernation of adult-sized Blanding's Turtles was studied at two west-central Wisconsin sites between 1991 and 2008. Turtles arrived at hibernacula from mid September to early October, spending 126 to 216 days at these sites, and generally emerged in early April yearly. Sixty percent of females and 30 percent of males hibernated in natural over man-made structures as hibernation sites. Anoxic conditions near five hibernation sites ranged from 78 to 100 days. Shell temperatures of three turtles monitored over five winters remained at <1°C a mean of 2,274 hours each winter. Over the same period, four turtles' temperatures were between 0° and -1°C a mean of 302 hours. During the course of our study, hibernating west-central Wisconsin Blanding's Turtles demonstrated a remarkable degree of both cold and anoxia-tolerance similar to that observed among Painted Turtles (Chrysemys picta) and Snapping Turtles (Chelydra serpentina).

scholarly journals From transcriptomics to metabolomics: Extracellular ATP induces TGF-β-like and TGF-β-independent epithelial mesenchymal transition in lung cancer cells

2021 ◽  
Author(s):  
Maria Evers ◽  
Jingwen Song ◽  
Pratik Shriwas ◽  
Harrison S Greenbaum ◽  
Xiaozhuo Chen
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Neutralizing Antibodies ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Extracellular Atp ◽  
Metabolic Reprogramming ◽  
Specific Gene ◽  
Mesenchymal Transition ◽  
Transcriptomic Changes

Abstract Background: Epithelial mesenchymal transition (EMT) is an early process in metastasis. Extracellular ATP (eATP) was shown to play important roles in EMT. However, the mechanisms by which eATP induces EMT and ATP’s relationship to TGF-b, a well-known EMT inducer, are unclear. Key questions include: if and how much EMT-specific gene expression eATP induces and how similar is ATP-induced EMT to TGF-b-induced EMT? We hypothesized that eATP acts as a specific inducer and regulator of EMT at all levels alternative to TGF-b in cancer cells. Methods: As EMT involves changes from gene expression to metabolites, RNAseq and metabolomics analyses were performed on human NSCLC A549 cells treated with either eATP or TGF-b to determine how they induce EMT at transcription and metabolic levels. Bio-functional assays, such as Transwell invasion, intracellular ATP, resazurin cell viability, fluorescence microscopy of filopodia formation, and antibody neutralization / cell rescue, were conducted in more NSCLC cell lines to validate changes identified from RNAseq and metabolomics analyses by confirming the corresponding EMT phenotypic changes.Results: RNAseq analysis shows that eATP significantly enriched expressions of genes involved in EMT temporarily, and similarly but non-identically to TGF-b after 2 and 6 hours of treatment. Eleven genes, with known or unknown functions in EMT, are significantly upregulated by both inducers at both time points, have been identified. Metabolomics analysis revealed eATP induced numerous EMT-related changes in metabolic pathways, including cytoskeleton rearrangement, glycolysis, glutaminolysis, ROS, and individual metabolic changes similar or identical to those induced by TGF-b. eATP-induced transcriptomic changes appeared smaller but earlier than TGF-b. Functional bioassays verified the RNAseq and metabolomics findings that eATP induced earlier and more invasion and formation of filopodia in A549 and H1299 cells, and restored viability of cancer cells treated with TGF-b-neutralizing antibodies. Conclusions: eATP-induced EMT, from gene expression changes and metabolic reprogramming, is similar but non-identical to that induced by TGF-b, and is independent of TGF-b. The smaller but earlier EMT-related changes induced by eATP, compared with TGF-b, could be largely explained by extracellular action of eATP and intracellular activities of macropinocytosis-internalized eATP. These strongly indicate that eATP is an emerging master inducer and regulator of EMT.

scholarly journals ROCK2 promotes osteosarcoma growth and glycolysis by up-regulating HKII via phospho- PI3K/AKT signalling

2020 ◽  
Author(s):  
Xue qaing Deng ◽  
Jianyong Deng ◽  
Xuan Yi ◽  
Yeqing Zou ◽  
Liang Hao
Keyword(s):  
Colony Formation ◽  
Aerobic Glycolysis ◽  
Bone Tumour ◽  
Lactate Production ◽  
Metabolic Stress ◽  
Glucose Consumption ◽  
Metabolic Reprogramming ◽  
Hexokinase Ii ◽  
Protein Expressions ◽  
Key Enzyme

Abstract Background Osteosarcoma (OS) is a malignant bone tumour that exhibits a high mortality. While tumours thrive in a state of malnutrition, the mechanism by which OS cells adapt to metabolic stress through metabolic reprogramming remains unclear. Methods We analysed the expression of ROCK2 in osteosarcoma patients by RT-qPCR and Western blot. Cell proliferation, and colony formation were analysed using CCK8, EdU assays and colony formation assays. The level of Cell glycolysis was detected by glucose-6 phosphate, glucose consumption, lactate production and ATP levels. Results Herein, our study showed that ROCK2 expression in OS was higher than in adjacent tissues. Functional assays have demonstrated that ROCK2 contributes to the growth of OS cells by inducing aerobic glycolysis. The current study revealed that ROCK2 knockdown decreased the levels of mitochondrial hexokinase II (HKII). And also indicated that ROCK2 served as a key enzyme in glycolysis and that it served an important role in tumour growth and metastasis. A significant positive correlation was identified between the mRNA and protein expressions of ROCK2 and HKII, further demonstrating that ROCK2-induced glycolysis and proliferation was dependent on HKII in OS cells. Mechanistically, ROCK2 promotes HKII expression by activating the phospho-PI3K/AKT signalling pathway. Conclusions Taken together, the results of the current study linked the two drivers of OS growth and aerobic glycolysis, and identified a new mechanism of ROCK2 control in OS.

scholarly journals High Expression of Glycolytic Genes in Clinical Glioblastoma Patients Correlates with Lower Survival

2021 ◽  
Author(s):  
Kimberly M Stanke ◽  
Carrick Wilson ◽  
Srivatsan Kidambi
Keyword(s):  
Gene Expression ◽  
Aerobic Glycolysis ◽  
Treatment Options ◽  
Lactate Production ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
High Expression ◽  
Low Grade ◽  
Normal Brain ◽  
Expression Levels

Glioblastoma (GBM), the most aggressive brain tumor, is associated with a median survival at diagnosis of 16-20 months and limited treatment options. The key hallmark of GBM is altered tumor metabolism and marked increase in the rate of glycolysis. Aerobic glycolysis along with elevated glucose consumption and lactate production supports rapid cell proliferation and GBM growth. In this study, we examined the gene expression profile of metabolic targets in GBM samples from patients with low grade glioma (LGG) and GBM. We found that gene expression of glycolytic enzymes is up-regulated in GBM samples and significantly associated with an elevated risk for developing GBM. Our findings of clinical outcomes showed that GBM patients with high expression of HK2 and PKM2 in the glycolysis related genes and low expression of genes involved in mitochondrial metabolism-SDHB and COX5A related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), respectively, was associated with poor patient overall survival. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in GBM compared to LGG but was lower compared to normal brain. The fact that in GBM the expression levels of TCA cycle and OXPHOS-related genes are higher than those in LGG patients suggests the metabolic shift in GBM cells when progressing from LGG to GBM. These results are an important step forward in our understanding of the role of metabolic reprogramming in glioma as drivers of the tumor and could be potential prognostic targets in GBM therapies.

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