Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.

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Evolved resistance to GAPDH inhibition results in loss of the Warburg Effect but retains a different state of glycolysis

10.1101/602557 ◽

2019 ◽

Cited By ~ 1

Author(s):

Maria V. Liberti ◽

Annamarie E. Allen ◽

Vijyendra Ramesh ◽

Ziwei Dai ◽

Katherine R. Singleton ◽

...

Keyword(s):

Glucose Metabolism ◽

Warburg Effect ◽

Acid Metabolism ◽

Aerobic Glycolysis ◽

Specific Inhibitor ◽

Central Carbon Metabolism ◽

Glycolytic Enzyme ◽

Altered State ◽

The Warburg Effect

SUMMARYAerobic glycolysis or the Warburg Effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although ubiquitous, the biological role of the WE remains controversial and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, we evolved resistance to koningic acid (KA), a natural product shown to be a specific inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme during the WE. We find that KA-resistant cells lose the WE but conduct glycolysis and surprisingly remain dependent on glucose and central carbon metabolism. Consequentially this altered state of glycolysis leads to differential metabolic activity and requirements including emergent activities in and dependencies on fatty acid metabolism. Together, these findings reveal that, contrary to some recent reports, aerobic glycolysis is a functionally distinct entity from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.

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Influence of SNF1 complex on growth, glucose metabolism and mitochondrial respiration ofSaccharomyces cerevisiae

10.1101/287961 ◽

2018 ◽

Author(s):

Cecilia Martinez-Ortiz ◽

Andres Carrillo-Garmendia ◽

Blanca Flor Correa-Romero ◽

Melina Canizal-García ◽

Juan Carlos González-Hernández ◽

...

Keyword(s):

Glucose Metabolism ◽

Mitochondrial Respiration ◽

Warburg Effect ◽

Gene Deletion ◽

Glycolytic Flux ◽

Crabtree Effect ◽

Main Pathway ◽

Molecular Etiology ◽

The Warburg Effect

AbstractThe switch of mitochondrial respiration to fermentation as the main pathway to produce ATP through the increase of glycolytic flux is known as the Crabtree effect. The elucidation of the molecular mechanism of the Crabtree effect may have important applications in ethanol production and lay the groundwork for the Warburg effect, which is essential in the molecular etiology of cancer. A key piece in this mechanism could be Snf1p, which is a protein that participates in the nutritional response that includes glucose metabolism. Thus, this work aimed to recognize the role of the SNF1 complex on the glycolytic flux and mitochondrial respiration, to gain insights about its relationship with the Crabtree effect. Herein, we found that inSaccharomyces cerevisiaecells grown at 1% glucose, mutation ofSNF1gene decreased glycolytic flux, increased NAD(P)H, enhancedHXK2gene transcription, and decreased mitochondrial respiration. Meanwhile, the same mutation increased the mitochondrial respiration of cells grown at 10% glucose. Moreover,SNF4gene deletion increased respiration and growth at 1% of glucose. In the case of theGAL83gene, we did not detect any change in mitochondrial respiration or growth. Altogether, these findings indicate thatSNF1is vital to switch from mitochondrial respiration to fermentation.

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Protein Carbonylation in Patients with Myelodysplastic Syndrome: An Opportunity for Deferasirox Therapy

Antioxidants ◽

10.3390/antiox8110508 ◽

2019 ◽

Vol 8 (11) ◽

pp. 508 ◽

Cited By ~ 3

Author(s):

Alba Rodríguez-García ◽

María Luz Morales ◽

Vanesa Garrido-García ◽

Irene García-Baquero ◽

Alejandra Leivas ◽

...

Keyword(s):

Oxidative Stress ◽

Target Gene ◽

Iron Chelator ◽

Protein Carbonylation ◽

Fine Tuning ◽

Self Renewal ◽

Proliferation And Differentiation ◽

P53 Target Gene ◽

And Control

Control of oxidative stress in the bone marrow (BM) is key for maintaining the interplay between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an indicator of oxidative stress in the BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox (DFX). As expected, differences in the pattern of protein carbonylation were observed in BM samples between MDS patients and controls, with an increase in protein carbonylation in the former. Strikingly, patients under DFX treatment had lower levels of protein carbonylation in BM with respect to untreated patients. Proteomic analysis identified four proteins with high carbonylation levels in MDS BM cells. Finally, as oxidative stress-related signaling pathways can modulate the cell cycle through p53, we analyzed the expression of the p53 target gene p21 in BM cells, finding that it was significantly upregulated in patients with MDS and was significantly downregulated after DFX treatment. Overall, our results suggest that the fine-tuning of oxidative stress levels in the BM of patients with MDS might control malignant progression.

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Hyperbaric Oxygen Therapy Represses the Warburg Effect and Epithelial–Mesenchymal Transition in Hypoxic NSCLC Cells via the HIF-1α/PFKP Axis

Frontiers in Oncology ◽

10.3389/fonc.2021.691762 ◽

2021 ◽

Vol 11 ◽

Author(s):

Linling Zhang ◽

Jingjing Ke ◽

Shengping Min ◽

Nan Wu ◽

Fei Liu ◽

...

Keyword(s):

Glucose Metabolism ◽

Cell Lines ◽

Hyperbaric Oxygen ◽

Hyperbaric Oxygen Therapy ◽

Warburg Effect ◽

Oxygen Therapy ◽

Nsclc Cell ◽

Glycolytic Flux ◽

Mesenchymal Transition ◽

The Warburg Effect

BackgroundTumor cells initiate hypoxia-induced mechanisms to fuel cell proliferation, invasion, and metastasis, largely mediated by low O2-responsive Hypoxia-Inducible Factor 1 Alpha (HIF-1α). Therefore, hyperbaric oxygen therapy (HBO) is now being studied in cancer patients, but its impact upon non-small-cell lung cancer (NSCLC) cell metabolism remains uncharacterized.MethodsWe employed the NSCLC cell lines A549 and H1299 for in vitro studies. Glucose uptake, pyruvate, lactate, and adenosine triphosphate (ATP) assays were used to assess aerobic glycolysis (Warburg effect). A quantitative glycolytic flux model was used to analyze the flux contributions of HIF-1α-induced glucose metabolism genes. We used a Lewis lung carcinoma (LLC) murine model to measure lung tumorigenesis in C57BL/6J mice.ResultsHBO suppressed hypoxia-induced HIF-1α expression and downstream HIF-1α signaling in NSCLC cells. One HIF-1α-induced glucose metabolism gene—Phosphofructokinase, Platelet (PFKP)—most profoundly enhanced glycolytic flux under both low- and high-glucose conditions. HBO suppressed hypoxia-induced PFKP transactivation and gene expression via HIF-1α downregulation. HBO’s suppression of the Warburg effect, suppression of hyperproliferation, and suppression of epithelial-to-mesenchymal transition (EMT) in hypoxic NSCLC cell lines is mediated by the HIF-1α/PFKP axis. In vivo, HBO therapy inhibited murine LLC lung tumor growth in a Pfkp-dependent manner.ConclusionsHBO’s repression of the Warburg effect, repression of hyperproliferation, and repression of EMT in hypoxic NSCLC cells is dependent upon HIF-1α downregulation. HIF-1α’s target gene PFKP functions as a central mediator of HBO’s effects in hypoxic NSCLC cells and may represent a metabolic vulnerability in NSCLC tumors.

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MYC regulates metabolism through vesicular transfer of glycolytic kinases

Open Biology ◽

10.1098/rsob.210276 ◽

2021 ◽

Vol 11 (12) ◽

Author(s):

Alexia Tsakaneli ◽

Victor Corasolla Carregari ◽

Martina Morini ◽

Alessandra Eva ◽

Giuliana Cangemi ◽

...

Keyword(s):

Warburg Effect ◽

Neuroblastoma Cells ◽

Mass Spectrometry Analysis ◽

Target Cells ◽

Hexokinase Ii ◽

Childhood Malignancy ◽

Spectrometry Analysis ◽

Functional Consequences ◽

The Warburg Effect

Amplification of the proto-oncogene MYCN is a key molecular aberration in high-risk neuroblastoma and predictive of poor outcome in this childhood malignancy. We investigated the role of MYCN in regulating the protein cargo of extracellular vesicles (EVs) secreted by tumour cells that can be internalized by recipient cells with functional consequences. Using a switchable MYCN system coupled to mass spectrometry analysis, we found that MYCN regulates distinct sets of proteins in the EVs secreted by neuroblastoma cells. EVs produced by MYCN-expressing cells or isolated from neuroblastoma patients induced the Warburg effect, proliferation and c-MYC expression in target cells. Mechanistically, we linked the cancer-promoting activity of EVs to the glycolytic kinase pyruvate kinase M2 (PKM2) that was enriched in EVs secreted by MYC-expressing neuroblastoma cells. Importantly, the glycolytic enzymes PKM2 and hexokinase II were detected in the EVs circulating in the bloodstream of neuroblastoma patients, but not in those of non-cancer children. We conclude that MYC-activated cancers might spread oncogenic signals to remote body locations through EVs.

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Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

10.1101/2021.09.07.459348 ◽

2021 ◽

Author(s):

Qiufang Yang ◽

Wenshan Zhao ◽

Yadi Xing ◽

Peng Li ◽

Xiaowen Zhou ◽

...

Keyword(s):

Glucose Metabolism ◽

Warburg Effect ◽

Metabolic Diseases ◽

Energy State ◽

Glucose Deprivation ◽

Cancer Development ◽

Energy Sensor ◽

Dual Sensor ◽

Glycolysis Pathway ◽

The Warburg Effect

AbstractNFE2L1 (also called Nrf1) acts a core regulator of redox signaling and metabolism homeostasis, and thus its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism is still elusive. Here, we found that the loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation. The uptake of glucose was also affected by NFE2L1 deficiency. Further experiments unveiled that although the glycosylation of NFE2L1 was monitored through the glycolysis pathway, it enabled to sense the energy state and directly interacted with AMPK. These indicate that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. In-depth sights into transcriptome, metabolome and seahorse data further unraveled that glucose metabolism was reprogrammed by disruption of NFE2L1, so as to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, along with the mitochondrial damage observed under the electron microscope. Collectively, these demonstrate that disfunction of NFE2L1 triggers the uncontrollable signaling by AMPK towards glucose metabolism reprogramming in the liver cancer development.

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An Anti-tumorigenic Role of the Warburg Effect at Emergence of Transformed Cells

Cell Structure and Function ◽

10.1247/csf.18018 ◽

2018 ◽

Vol 43 (2) ◽

pp. 171-176 ◽

Cited By ~ 2

Author(s):

Kojiro Ishibashi ◽

Riku Egami ◽

Kazuki Nakai ◽

Shunsuke Kon

Keyword(s):

Warburg Effect ◽

Transformed Cells ◽

The Warburg Effect

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Role of p53 Serine 46 in p53 Target Gene Regulation

PLoS ONE ◽

10.1371/journal.pone.0017574 ◽

2011 ◽

Vol 6 (3) ◽

pp. e17574 ◽

Cited By ~ 103

Author(s):

Leonie Smeenk ◽

Simon J. van Heeringen ◽

Max Koeppel ◽

Bianca Gilbert ◽

Eva Janssen-Megens ◽

...

Keyword(s):

Gene Regulation ◽

Target Gene ◽

P53 Target Gene

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Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling

Molecular Medicine ◽

10.1186/s10020-021-00300-8 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Jing Cui ◽

Yao Guo ◽

Heshui Wu ◽

Jiongxin Xiong ◽

Tao Peng

Keyword(s):

Pancreatic Cancer ◽

Glucose Metabolism ◽

Cell Viability ◽

Cancer Cells ◽

Warburg Effect ◽

Aerobic Glycolysis ◽

Mtor Signaling ◽

Glucose Transporter 1 ◽

Pancreatic Cancer Cells ◽

The Warburg Effect

Abstract Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

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