scholarly journals Vnn1 pantetheinase limits the Warburg effect and sarcoma growth by rescuing mitochondrial activity

2018 ◽  
Vol 1 (4) ◽  
pp. e201800073 ◽  
Author(s):  
Caroline Giessner ◽  
Virginie Millet ◽  
Konrad J Mostert ◽  
Thomas Gensollen ◽  
Thien-Phong Vu Manh ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Warburg Effect ◽  
Soft Tissue Sarcomas ◽  
Mitochondrial Activity ◽  
Cellular Energy ◽  
Aggressive Tumors ◽  
The Impact ◽  
The Warburg Effect

Like other tumors, aggressive soft tissue sarcomas (STS) use glycolysis rather than mitochondrial oxidative phosphorylation (OXPHOS) for growth. Given the importance of the cofactor coenzyme A (CoA) in energy metabolism, we investigated the impact of Vnn1 pantetheinase—an enzyme that degrades pantetheine into pantothenate (vitamin B5, the CoA biosynthetic precursor) and cysyteamine—on tumor growth. Using two models, we show that Vnn1+STS remain differentiated and grow slowly, and that in patients a detectable level of VNN1 expression in STS is associated with an improved prognosis. Increasing pantetheinase activity in aggressive tumors limits their growth. Using combined approaches, we demonstrate that Vnn1 permits restoration of CoA pools, thereby maintaining OXPHOS. The simultaneous production of cysteamine limits glycolysis and release of lactate, resulting in a partial inhibition of STS growth in vitro and in vivo. We propose that the Warburg effect observed in aggressive STS is reversed by induction of Vnn1 pantetheinase and the rewiring of cellular energy metabolism by its products.

scholarly journals CircECE1 activates energy metabolism in osteosarcoma by stabilizing c-Myc

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Shuying Shen ◽  
Teng Yao ◽  
Yining Xu ◽  
Deguang Zhang ◽  
Shunwu Fan ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Warburg Effect ◽  
Critical Role ◽  
Circular Rna ◽  
Molecular Therapy ◽  
Circular Rnas ◽  
Rna Immunoprecipitation ◽  
The Warburg Effect

Abstract Background Osteosarcoma (OS) is the most common malignant bone tumor and has a poor prognosis. The potential involvement of circular RNAs (circRNAs) in OS progression remains unexplored. Here, we report that CircECE1, a circular RNA derived from human ECE1, plays a critical role in energy metabolism in OS. Methods The RIP chip sequence assay was performed to confirm CircECE1, through overexpression or knockdown of CircECE1 to verify its function in 143B and U2OS. RNA immunoprecipitation and immunoprecipitation were used to verify CircECE1’s regulation of protein c-Myc and co- immunoprecipitation was used to verified the competitive binding relationship between CircECE1 and SPOP. The influence of CircECE1 on energy metabolism was evaluated by seahorse experiment, western blot, and immunohistochemistry. Results We found that CircECE1 is highly expressed in OS tissues and cells and that CircECE1 knockdown suppresses tumor proliferation and metastasis both in vitro and in vivo. Further, CircECE1 significantly promotes glucose metabolism in OS cells in vitro and in vivo. Mechanistically, CircECE1 interacts with c-Myc to prevent speckle-type POZ-mediated c-Myc ubiquitination and degradation. C-Myc inhibits thioredoxin binding protein (TXNIP) transcription and subsequently activates the Warburg effect. Conclusions CircECE1 regulates the Warburg effect through the c-Myc/TXNIP axis. CircECE1 mediated signal transduction plays a important role in OS process and energy metabolism. These findings may identify novel targets for OS molecular therapy.

scholarly journals Proton export drives the Warburg Effect

2021 ◽  
Author(s):  
Shonagh Russell ◽  
Liping Xu ◽  
Yoonseok Kam ◽  
Dominique Abrahams ◽  
Bryce Ordway ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Glycolytic Enzymes ◽  
Hek293 Cells ◽  
Driver Mutations ◽  
The Warburg Effect

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

scholarly journals Breed-specific factors influence embryonic lipid composition: comparison between Jersey and Holstein

2016 ◽  
Vol 28 (8) ◽  
pp. 1185 ◽  
Author(s):  
Luis Baldoceda ◽  
Isabelle Gilbert ◽  
Dominic Gagné ◽  
Christian Vigneault ◽  
Patrick Blondin ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Lipid Composition ◽  
Lipid Droplets ◽  
Cell Damage ◽  
Poor Performance ◽  
Culture Conditions ◽  
Mitochondrial Activity ◽  
The Impact

Some embryos exhibit better survival potential to cryopreservation than others. The cause of such a phenotype is still unclear and may be due to cell damage during cryopreservation, resulting from overaccumulation and composition of lipids. In cattle embryos, in vitro culture conditions have been shown to impact the number of lipid droplets within blastomeres. Thus far, the impact of breed on embryonic lipid content has not been studied. In the present study were compared the colour, lipid droplet abundance, lipid composition, mitochondrial activity and gene expression of in vivo-collected Jersey breed embryos, which are known to display poor performance post-freezing, with those of in vivo Holstein embryos, which have good cryotolerance. Even when housed and fed under the same conditions, Jersey embryos were found to be darker and contain more lipid droplets than Holstein embryos, and this was correlated with lower mitochondrial activity. Differential expression of genes associated with lipid metabolism and differences in lipid composition were found. These results show genetic background can impact embryonic lipid metabolism and storage.

scholarly journals Author Correction: Mito-oncology agent: fermented extract suppresses the Warburg effect, restores oxidative mitochondrial activity, and inhibits in vivo tumor growth

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gyula Bencze ◽  
Szilvia Bencze ◽  
Keith D. Rivera ◽  
James D. Watson ◽  
Mate Hidvegi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Warburg Effect ◽  
Mitochondrial Activity ◽  
The Warburg Effect

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1662
Author(s):  
Alejandra Ortiz-Ruiz ◽  
Yanira Ruiz-Heredia ◽  
María Luz Morales ◽  
Pedro Aguilar-Garrido ◽  
Almudena García-Ortiz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Increase ◽  
Mitochondrial Activity ◽  
Hematological Cancers ◽  
Frontline Treatment ◽  
Novel Target ◽  
The Impact ◽  
Mitochondrial Inhibitor

Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitochondrial inhibitor, tigecycline, to overcome MM proliferation. COXII expression, COX activity, mitochondrial mass, and mitochondrial membrane potential demonstrated a progressive increase of mitochondrial features as the disease progresses. In vitro and in vivo therapeutic targeting using the mitochondrial inhibitor tigecycline showed promising efficacy and cytotoxicity in monotherapy and combination with the MM frontline treatment bortezomib. Overall, our findings demonstrate how mitochondrial activity emerges in MM transformation and disease progression and the efficacy of therapies targeting these novel vulnerabilities.

scholarly journals Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism

2018 ◽  
Vol 293 (41) ◽  
pp. 15947-15961 ◽  
Author(s):  
Maša Ždralević ◽  
Almut Brand ◽  
Lorenza Di Ianni ◽  
Katja Dettmer ◽  
Jörg Reinders ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Warburg Effect ◽  
Specific Inhibitor ◽  
Glucose Consumption ◽  
Glycolytic Enzyme ◽  
Double Knockout ◽  
Genetic Block ◽  
The Warburg Effect

Increased glucose consumption distinguishes cancer cells from normal cells and is known as the “Warburg effect” because of increased glycolysis. Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme, a hallmark of aggressive cancers, and believed to be the major enzyme responsible for pyruvate-to-lactate conversion. To elucidate its role in tumor growth, we disrupted both the LDHA and LDHB genes in two cancer cell lines (human colon adenocarcinoma and murine melanoma cells). Surprisingly, neither LDHA nor LDHB knockout strongly reduced lactate secretion. In contrast, double knockout (LDHA/B-DKO) fully suppressed LDH activity and lactate secretion. Furthermore, under normoxia, LDHA/B-DKO cells survived the genetic block by shifting their metabolism to oxidative phosphorylation (OXPHOS), entailing a 2-fold reduction in proliferation rates in vitro and in vivo compared with their WT counterparts. Under hypoxia (1% oxygen), however, LDHA/B suppression completely abolished in vitro growth, consistent with the reliance on OXPHOS. Interestingly, activation of the respiratory capacity operated by the LDHA/B-DKO genetic block as well as the resilient growth were not consequences of long-term adaptation. They could be reproduced pharmacologically by treating WT cells with an LDHA/B-specific inhibitor (GNE-140). These findings demonstrate that the Warburg effect is not only based on high LDHA expression, as both LDHA and LDHB need to be deleted to suppress fermentative glycolysis. Finally, we demonstrate that the Warburg effect is dispensable even in aggressive tumors and that the metabolic shift to OXPHOS caused by LDHA/B genetic disruptions is responsible for the tumors' escape and growth.

scholarly journals SIRT5 functions as a tumor suppressor in renal cell carcinoma by reversing the Warburg effect

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Liu Yihan ◽  
Wang Xiaojing ◽  
Liu Ao ◽  
Zhang Chuanjie ◽  
Wang Haofei ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Western Blotting ◽  
Renal Cell ◽  
Warburg Effect ◽  
Clear Cell ◽  
In Vivo Experiments ◽  
The Warburg Effect

Abstract Background The aim of this study was to investigate the biological functions and underlying mechanisms of SIRT5 in clear cell renal cell carcinoma (ccRCC). Methods SIRT5 expression data in The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) were selected, and the correlations between SIRT5 expression and various clinicopathological parameters were analysed. SIRT5 expression in ccRCC tissues was examined using immunohistochemistry. Stable cell lines with SIRT5 knockdown were established. In vitro and in vivo experiments were conducted to investigate the functional roles of SIRT5 in the cellular biology of ccRCC, including cell viability assays, wound healing assays, soft agar colony formation assays, Transwell invasion assays, qRT–PCR, and Western blotting. In addition, microarrays, rescue experiments and Western blotting were used to investigate the molecular mechanisms underlying SIRT5 functions. Results SIRT5 expression was downregulated in ccRCC compared with normal tissues, which correlated with a poor prognosis of ccRCC. SIRT5 knockdown significantly increased cell proliferation, migration and invasion in vitro. In vivo experiments revealed that SIRT5 knockdown promoted ccRCC tumorigenesis and metastasis. Mechanistically, SIRT5 deglycosylated PDHA1 at K351 and increased PDC activity, thereby altering the metabolic crosstalk with the TCA cycle and inhibiting the Warburg effect. SIRT5 overexpression was related to low succinylation of PDHA1. Conclusions Downregulated SIRT5 expression in ccRCC accelerated the Warburg effect through PDHA1 hypersuccinylation and induced tumorigenesis and progression, indicating that SIRT5 may become a potential target for ccRCC therapy.

scholarly journals LncRNA OIP5-AS1 Regulates the Warburg Effect Through miR-124-5p/IDH2/HIF-1α Pathway in Cervical Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Li Li ◽  
Yan Ma ◽  
Kamalibaike Maerkeya ◽  
Davuti Reyanguly ◽  
Lili Han
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Warburg Effect ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Cervical Cancer Cells ◽  
The Warburg Effect

Hypoxia reprogrammed glucose metabolism affects the Warburg effect of tumor cells, but the mechanism is still unclear. Long-chain non-coding RNA (lncRNA) has been found by many studies to be involved in the Warburg effect of tumor cells under hypoxic condition. Herein, we find that lncRNA OIP5-AS1 is up-regulated in cervical cancer tissues and predicts poor 5-years overall survival in cervical cancer patients, and it promotes cell proliferation of cervical cancer cells in vitro and in vivo. Moreover, OIP5-AS1 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis which is IDH2 or hypoxia inducible factor-1α (HIF-1α) dependent. In cervical cancer cells, OIP5-AS1 promotes IDH2 expression by inhibiting miR-124-5p, and IDH2 promotes the Warburg effect of cervical under hypoxic condition through regulating HIF-1α expression. In conclusion, hypoxia induced OIP5-AS1 promotes the Warburg effect through miR-124-5p/IDH2/HIF-1α pathway in cervical cancer.

scholarly journals Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Chen ◽  
Xu Cao ◽  
Bolei Li ◽  
Zhangchen Zhao ◽  
Siqi Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Evasion ◽  
Warburg Effect ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
Extracellular Acidification ◽  
Extracellular Medium ◽  
The Warburg Effect

Evasion of immunosurveillance is critical for cancer initiation and development. The expression of “don’t eat me” signals protects cancer cells from being phagocytosed by macrophages, and the blockade of such signals demonstrates therapeutic potential by restoring the susceptibility of cancer cells to macrophage-mediated phagocytosis. However, whether additional self-protective mechanisms play a role against macrophage surveillance remains unexplored. Here, we derived a macrophage-resistant cancer model from cells deficient in the expression of CD47, a major “don’t eat me” signal, via a macrophage selection assay. Comparative studies performed between the parental and resistant cells identified self-protective traits independent of CD47, which were examined with both pharmacological or genetic approaches in in vitro phagocytosis assays and in vivo tumor models for their roles in protecting against macrophage surveillance. Here we demonstrated that extracellular acidification resulting from glycolysis in cancer cells protected them against macrophage-mediated phagocytosis. The acidic tumor microenvironment resulted in direct inhibition of macrophage phagocytic ability and recruitment of weakly phagocytic macrophages. Targeting V-ATPase which transports excessive protons in cancer cells to acidify extracellular medium elicited a pro-phagocytic microenvironment with an increased ratio of M1-/M2-like macrophage populations, therefore inhibiting tumor development and metastasis. In addition, blockade of extracellular acidification enhanced cell surface exposure of CD71, targeting which by antibodies promoted cancer cell phagocytosis. Our results reveal that extracellular acidification due to the Warburg effect confers immune evasion ability on cancer cells. This previously unrecognized role highlights the components mediating the Warburg effect as potential targets for new immunotherapy harnessing the tumoricidal capabilities of macrophages.

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