scholarly journals Sperm-specific COX6B2 enhances oxidative phosphorylation, proliferation, and survival in lung adenocarcinoma

2020 ◽  
Author(s):  
Chun-Chun Cheng ◽  
Joshua Wooten ◽  
Zane Gibbs ◽  
Kathleen McGlynn ◽  
Prashant Mishra ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Lung Adenocarcinoma ◽  
Cell Metabolism ◽  
Low Oxygen ◽  
Complex Iv ◽  
Cancer Testis Antigens ◽  
Oxygen Conditions ◽  
Necessary And Sufficient ◽  
Proliferative Advantage

ABSTRACTCancer testis antigens (CTAs) are genes whose expression is normally restricted to the testis but anomalously activated in cancer. In sperm, a number of CTAs promote energy generation, however whether these proteins contribute to tumor cell metabolism is not understood. Here we describe COX6B2, a sperm-specific component of cytochrome c oxidase (complex IV). COX6B2 is frequently expressed in human lung adenocarcinoma (LUAD) and expression correlates with reduced survival time in patients. COX6B2, but not its somatic isoform COX6B1, enhances activity of complex IV, increasing mitochondrial oxidative phosphorylation (OXPHOS) and NAD+ generation.Consequently, COX6B2-expressing cells display a proliferative advantage, particularly in low oxygen conditions. Conversely, depletion of COX6B2 attenuates OXPHOS and collapses mitochondrial membrane potential leading to cell death or senescence.Furthermore, COX6B2 is both necessary and sufficient for growth of tumors in vivo. Our findings reveal a previously unappreciated, tumor specific metabolic pathway hijacked from one of the most ATP-intensive processes in the animal kingdom: sperm motility.

scholarly journals Sperm-specific COX6B2 enhances oxidative phosphorylation, proliferation, and survival in human lung adenocarcinoma

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chun-Chun Cheng ◽  
Joshua Wooten ◽  
Zane A Gibbs ◽  
Kathleen McGlynn ◽  
Prashant Mishra ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Human Cancer ◽  
Human Tumor ◽  
Low Oxygen ◽  
Complex Iv ◽  
Human Lung Adenocarcinoma ◽  
Cancer Testis Antigens ◽  
Necessary And Sufficient

Cancer testis antigens (CTAs) are proteins whose expression is normally restricted to the testis but anomalously activated in human cancer. In sperm, a number of CTAs support energy generation, however, whether they contribute to tumor metabolism is not understood. We describe human COX6B2, a component of cytochrome c oxidase (complex IV). COX6B2 is expressed in human lung adenocarcinoma (LUAD) and expression correlates with reduced survival time. COX6B2, but not its somatic isoform COX6B1, enhances activity of complex IV, increasing oxidative phosphorylation (OXPHOS) and NAD+ generation. Consequently, COX6B2-expressing cancer cells display a proliferative advantage, particularly in low oxygen. Conversely, depletion of COX6B2 attenuates OXPHOS and collapses mitochondrial membrane potential leading to cell death or senescence. COX6B2 is both necessary and sufficient for growth of human tumor xenografts in mice. Our findings reveal a previously unappreciated, tumor-specific metabolic pathway hijacked from one of the most ATP-intensive processes in the animal kingdom: sperm motility.

scholarly journals Metabolic Signatures of Cryptosporidium parvum-Infected HCT-8 Cells and Impact of Selected Metabolic Inhibitors on C. parvum Infection under Physioxia and Hyperoxia

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 60
Author(s):  
Juan Vélez ◽  
Zahady Velasquez ◽  
Liliana M. R. Silva ◽  
Ulrich Gärtner ◽  
Klaus Failing ◽  
...  
Keyword(s):  
Host Cell ◽  
Cryptosporidium Parvum ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Glucose Consumption ◽  
Host Cells ◽  
Metabolic Inhibitors ◽  
Low Oxygen ◽  
Metabolic Signatures

Cryptosporidium parvum is an apicomplexan zoonotic parasite recognized as the second leading-cause of diarrhoea-induced mortality in children. In contrast to other apicomplexans, C.parvum has minimalistic metabolic capacities which are almost exclusively based on glycolysis. Consequently, C. parvum is highly dependent on its host cell metabolism. In vivo (within the intestine) infected epithelial host cells are typically exposed to low oxygen pressure (1–11% O2, termed physioxia). Here, we comparatively analyzed the metabolic signatures of C. parvum-infected HCT-8 cells cultured under both, hyperoxia (21% O2), representing the standard oxygen condition used in most experimental settings, and physioxia (5% O2), to be closer to the in vivo situation. The most pronounced effect of C. parvum infection on host cell metabolism was, on one side, an increase in glucose and glutamine uptake, and on the other side, an increase in lactate release. When cultured in a glutamine-deficient medium, C. parvum infection led to a massive increase in glucose consumption and lactate production. Together, these results point to the important role of both glycolysis and glutaminolysis during C. parvum intracellular replication. Referring to obtained metabolic signatures, we targeted glycolysis as well as glutaminolysis in C. parvum-infected host cells by using the inhibitors lonidamine [inhibitor of hexokinase, mitochondrial carrier protein (MCP) and monocarboxylate transporters (MCT) 1, 2, 4], galloflavin (lactate dehydrogenase inhibitor), syrosingopine (MCT1- and MCT4 inhibitor) and compound 968 (glutaminase inhibitor) under hyperoxic and physioxic conditions. In line with metabolic signatures, all inhibitors significantly reduced parasite replication under both oxygen conditions, thereby proving both energy-related metabolic pathways, glycolysis and glutaminolysis, but also lactate export mechanisms via MCTs as pivotal for C. parvum under in vivo physioxic conditions of mammals.

scholarly journals Hypoxic-response elements in the oncolytic parvovirus Minute virus of mice do not allow for increased vector production at low oxygen concentration

2006 ◽  
Vol 87 (5) ◽  
pp. 1197-1201 ◽  
Author(s):  
Charlotte Servais ◽  
Perrine Caillet-Fauquet ◽  
Marie-Louise Draps ◽  
Thierry Velu ◽  
Yvan de Launoit ◽  
...  
Keyword(s):  
Cell Metabolism ◽  
Consensus Sequence ◽  
High Titre ◽  
Host Cells ◽  
Low Oxygen ◽  
Minute Virus Of Mice ◽  
Minute Virus ◽  
Responsive Element ◽  
Low Oxygen Concentration

Vectors derived from the autonomous parvovirus Minute virus of mice, MVM(p), are promising tools for the gene therapy of cancer. The validation of their in vivo anti-tumour effect is, however, hampered by the difficulty to produce high-titre stocks. In an attempt to increase vector titres, host cells were subjected to low oxygen tension (hypoxia). It has been shown that a number of viruses are produced at higher titres under these conditions. This is the case, among others, for another member of the family Parvoviridae, the erythrovirus B19 virus. Hypoxia stabilizes a hypoxia-inducible transcription factor (HIF-1α) that interacts with a ‘hypoxia-responsive element’ (HRE), the consensus sequence of which (A/GCGTG) is present in the B19 and MVM promoters. Whilst the native P4 promoter was induced weakly in hypoxia, vector production was reduced dramatically, and adding HRE elements to the P4 promoter of the vector did not alleviate this reduction. Hypoxia has many effects on cell metabolism. Therefore, even if the P4 promoter is activated, the cellular factors that are required for the completion of the parvoviral life cycle may not be expressed.

scholarly journals Succinate Supplement Elicited “Pseudohypoxia” Condition to Promote Proliferation, Migration, and Osteogenesis of Periodontal Ligament Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Huimin Mao ◽  
Andi Yang ◽  
Yunhe Zhao ◽  
Lang Lei ◽  
Houxuan Li
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Oxidative Phosphorylation ◽  
Periodontal Ligament ◽  
Cell Metabolism ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Periodontal Ligament Cells ◽  
Low Oxygen

Most mesenchymal stem cells reside in a niche of low oxygen tension. Iron-chelating agents such as CoCl2 and deferoxamine have been utilized to mimic hypoxia and promote cell growth. The purpose of the present study was to explore whether a supplement of succinate, a natural metabolite of the tricarboxylic acid (TCA) cycle, can mimic hypoxia condition to promote human periodontal ligament cells (hPDLCs). Culturing hPDLCs in hypoxia condition promoted cell proliferation, migration, and osteogenic differentiation; moreover, hypoxia shifted cell metabolism from oxidative phosphorylation to glycolysis with accumulation of succinate in the cytosol and its release into culture supernatants. The succinate supplement enhanced hPDLC proliferation, migration, and osteogenesis with decreased succinate dehydrogenase (SDH) expression and activity, as well as increased hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), suggesting metabolic reprogramming from oxidative phosphorylation to glycolysis in a normal oxygen condition. The succinate supplement in cell cultures promoted intracellular succinate accumulation while stabilizing hypoxia inducible factor-1α (HIF-1α), leading to a state of pseudohypoxia. Moreover, we demonstrate that hypoxia-induced proliferation was G-protein-coupled receptor 91- (GPR91-) dependent, while exogenous succinate-elicited proliferation involved the GPR91-dependent and GPR91-independent pathway. In conclusion, the succinate supplement altered cell metabolism in hPDLCs, induced a pseudohypoxia condition, and enhanced proliferation, migration, and osteogenesis of mesenchymal stem cells in vitro.

scholarly journals Emergent Bacteria in Cystic Fibrosis:In VitroBiofilm Formation and Resilience under Variable Oxygen Conditions

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Susana P. Lopes ◽  
Nuno F. Azevedo ◽  
Maria O. Pereira
Keyword(s):  
Bacterial Species ◽  
Low Oxygen ◽  
Antibiotic Susceptibilities ◽  
Oxygen Conditions ◽  
Mode Of Life ◽  
Lung Infections ◽  
Biofilm Development ◽  
The Impact

Concurrent to conventional bacterial pathogens, unusual microbes are emerging from cystic fibrosis (CF) airways. Nonetheless, little is known about the contribution of these newly microbes to the resilience of CF-associated biofilms, particularly under variable-oxygen concentrations that are known to occurin vivoin the mucus of CF patients. Two CF-emergent bacterial species,Inquilinus limosusandDolosigranulum pigrum, and the major pathogenPseudomonas aeruginosawere studied in terms of biofilm development and antibiotic susceptibilities underin vitroatmospheres with different oxygen availabilities. All species were able to developin vitrobiofilms under different oxygen-available environments, withD. pigrumaccumulating high amounts of biomass and respiratory activities. When established, biofilms were of difficult eradication, with antibiotics losing their effectiveness in comparison with the corresponding planktonic populations. Surprisingly, biofilms of each emergent organism displayed multidrug resistance under aerobic environments, enduring even in low-oxygen atmospheres. This study suggests a potential prospect on the impact of nonconventional organismsI. limosusandD. pigrumon CF lung infections, demonstrating capacity to adapt to biofilm mode of life under restricted-oxygen atmospheres resembling CF airways, which may ultimately endanger the efficacy of currently used antibiotic regimens.

scholarly journals Hypoxic Transformation of Immune Cell Metabolism Within the Microenvironment of Oral Cancers

2020 ◽  
Vol 1 ◽  
Author(s):  
Amrita Chaudhary ◽  
Swarnendu Bag ◽  
Neeraj Arora ◽  
Vivek S. Radhakrishnan ◽  
Deepak Mishra ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Metabolism ◽  
Redox Homeostasis ◽  
Oxygen Depletion ◽  
Metabolic Reprogramming ◽  
Low Oxygen ◽  
Oral Cancers ◽  
Oxygen Conditions

Oral squamous cell carcinoma (OSCC) includes tumors of the lips, tongue, gingivobuccal complex, and floor of the mouth. Prognosis for OSCC is highly heterogeneous, with overall 5-year survival of ~50%, but median survival of just 8–10 months for patients with locoregional recurrence or metastatic disease. A key feature of OSCC is microenvironmental oxygen depletion due to rapid growth of constituent tumor cells, which triggers hypoxia-associated signaling events and metabolic adaptations that influence subsequent tumor progression. Better understanding of leukocyte responses to tissue hypoxia and onco-metabolite expression under low-oxygen conditions will therefore be essential to develop more effective methods of diagnosing and treating patients with OSCC. This review assesses recent literature on metabolic reprogramming, redox homeostasis, and associated signaling pathways that mediate crosstalk of OSCC with immune cells in the hypoxic tumor microenvironment. The likely functional consequences of this metabolic interface between oxygen-starved OSCC and infiltrating leukocytes are also discussed. The hypoxic microenvironment of OSCC modifies redox signaling and alters the metabolic profile of tumor-infiltrating immune cells. Improved understanding of heterotypic interactions between host leukocytes, tumor cells, and hypoxia-induced onco-metabolites will inform the development of novel theranostic strategies for OSCC.

scholarly journals Isolation and Characterization of Bacteriophages That Infect Citrobacter rodentium, a Model Pathogen for Intestinal Diseases

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 737
Author(s):  
Carolina M. Mizuno ◽  
Tiffany Luong ◽  
Robert Cederstrom ◽  
Mart Krupovic ◽  
Laurent Debarbieux ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Phage Therapy ◽  
Lytic Cycle ◽  
Citrobacter Rodentium ◽  
Low Oxygen ◽  
In Vivo Models ◽  
Isolation And Characterization ◽  
Oxygen Conditions ◽  
Phage Strain

Enteropathogenic Escherichia coli (EPEC) is a major pathogen for diarrheal diseases among children. Antibiotics, when used appropriately, are effective; however, their overuse and misuse have led to the rise of antibiotic resistance worldwide. Thus, there are renewed efforts into the development of phage therapy as an alternative antibacterial therapy. Because EPEC in vivo models have shortcomings, a surrogate is used to study the mouse pathogen Citrobacter rodentium in animal models. In this study, two new phages CrRp3 and CrRp10, which infect C. rodentium, were isolated and characterized. CrRp3 was found to be a new species within the genus Vectrevirus, and CrRp10 is a new strain within the species Escherichia virus Ime09, in the genus Tequatrovirus. Both phages appear to have independently evolved from E. coli phages, rather than other Citrobacter spp. phages. Neither phage strain carries known genes associated with bacterial virulence, antibiotic resistance, or lysogeny. CrRp3 is more potent, having a 24-fold faster adsorption rate and shorter lytic cycle when compared to the same properties of CrRp10. However, a lysis curve analysis revealed that CrRp10 prevented growth of C. rodentium for 18 h, whereas resistance developed against CrRp3 within 9 h. We also show that hypoxic (5% oxygen) conditions decreased CrRp3 ability to control bacterial densities in culture. In contrast, low oxygen conditions did not affect CrRp10 ability to replicate on C. rodentium. Together, CrRp10 is likely to be the better candidate for future phage therapy investigations.

scholarly journals MAGE-A1 in lung adenocarcinoma as a promising target of chimeric antigen receptor T cells

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuan Mao ◽  
Weifei Fan ◽  
Hao Hu ◽  
Louqian Zhang ◽  
Jerod Michel ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Adenocarcinoma ◽  
Lentiviral Vector ◽  
Car T Cell ◽  
Cancer Testis Antigens ◽  
Cell Immunotherapy ◽  
Promising Target ◽  
Car T

Abstract Background Cancer/testis antigens (CTAs) are a special type of tumor antigen and are believed to act as potential targets for cancer immunotherapy. Methods In this study, we first screened a rational CTA MAGE-A1 for lung adenocarcinoma (LUAD) and explored the detailed characteristics of MAGE-A1 in LUAD development through a series of phenotypic experiments. Then, we developed a novel MAGE-A1-CAR-T cell (mCART) using lentiviral vector based on our previous MAGE-A1-scFv. The anti-tumor effects of this mCART were finally investigated in vitro and in vivo. Results The results showed striking malignant behaviors of MAGE-A1 in LUAD development, which further validated the rationality of MAGE-A1 as an appropriate target for LUAD treatment. Then, the innovative mCART was successfully constructed, and mCART displayed encouraging tumor-inhibitory efficacy in LUAD cells and xenografts. Conclusions Taken together, our data suggest that MAGE-A1 is a promising candidate marker for LUAD therapy and the MAGE-A1-specific CAR-T cell immunotherapy may be an effective strategy for the treatment of MAGE-A1-positive LUAD.

scholarly journals A Family of acr-Coregulated Mycobacterium tuberculosis Genes Shares a Common DNA Motif and Requires Rv3133c (dosR or devR) for Expression

2003 ◽  
Vol 71 (9) ◽  
pp. 5332-5343 ◽  
Author(s):  
Matthew A. Florczyk ◽  
Lee Ann McCue ◽  
Anjan Purkayastha ◽  
Egidio Currenti ◽  
Meyer J. Wolin ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Fluorescent Protein ◽  
Culture Conditions ◽  
Sequence Motif ◽  
Low Oxygen ◽  
Protein Fusion ◽  
Dna Motif ◽  
Oxygen Conditions ◽  
Green Fluorescent

ABSTRACT Previous work has shown that the divergently transcribed Mycobacterium tuberculosis genes acr (hspX, Rv2031c) and acg (Rv2032) are induced under conditions of shallow standing culture and low oxygen and intracellularly within macrophages. We used a combination of computational and experimental methods to identify promoters for eight additional genes that are regulated in a similar manner and that comprise an acr-coregulated promoter (ACP) family. Transcriptional regulation of these ACP family members was evaluated by using a plasmid-based promoter-green fluorescent protein fusion system and flow cytometry. All promoters showed increased expression in shallow standing versus shaking cultures, in low- versus high-oxygen conditions, and intracellularly within macrophages versus extracellularly in tissue culture medium. However, there were quantitative differences in expression among promoters and among conditions for each promoter. A conserved 18-bp palindromic sequence motif was identified in all ACPs by Gibbs sampling-based computational analyses. Two such motifs overlap regions in the acr and acg promoters that were previously shown to be required for their expression. In addition, we found that 5% carbon dioxide was required for growth of Mycobacterium bovis BCG under microaerophilic (1.3% O2) culture conditions and fully prevented the growth cessation typically associated with rapid removal of oxygen. These findings are likely to be relevant to the in vivo environment and will contribute to our understanding of the pathogenesis of tuberculosis infection.

Towards Engineering Whole Bones via Endochondral Ossification

2013 ◽  
Author(s):  
Eamon J. Sheehy ◽  
Tatiana Vinardell ◽  
Conor T. Buckley ◽  
Daniel J. Kelly
Keyword(s):  
Tissue Engineering ◽  
Bone Tissue Engineering ◽  
Bone Tissue ◽  
Three Dimensional ◽  
Low Oxygen ◽  
Engineering Applications ◽  
Endochondral Bone ◽  
Oxygen Conditions

Tissue engineering applications aim to replace or regenerate damaged tissues through a combination of cells, three-dimensional scaffolds, and signaling molecules [1]. The endochondral approach to bone tissue engineering [2], which involves remodeling of an intermittent hypertrophic cartilaginous template, may be superior to the traditional intramembranous approach. Naturally derived hydrogels have been used extensively in tissue engineering applications [3]. Mesenchymal stem cell (MSC) seeded hydrogels may be a particularly powerful tool in scaling-up engineered endochondral bone grafts as the low oxygen conditions that develop within large constructs enhance in vitro chondrogenic differentiation and functional development [4]. A key requirement however, is that the hydrogel must allow for remodeling of the engineered hypertrophic cartilage into bone and also facilitate vascularization of the graft. The first objective of this study was to compare the capacity of different naturally derived hydrogels (alginate, chitosan, and fibrin) to generate in vivo endochondral bone. The secondary objective was to investigate the possibility of engineering a ‘scaled-up’ anatomically accurate distal phalange as a paradigm for whole bone tissue engineering.

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