scholarly journals Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas

2021 ◽  
Vol 22 (14) ◽  
pp. 7265
Author(s):  
Kristina M. Cook ◽  
Han Shen ◽  
Kelly J. McKelvey ◽  
Harriet E. Gee ◽  
Eric Hau
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
High Grade Glioma ◽  
Glycolytic Flux ◽  
High Grade ◽  
Dna Breaks ◽  
Novel Approach ◽  
Altered Glucose ◽  
Altered Metabolism ◽  
The Warburg Effect

As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA’s pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.

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

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.

scholarly journals Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy

2021 ◽  
Vol 28 ◽  
pp. 107327482110412
Author(s):  
Karolina Kozal ◽  
Paweł Jóźwiak ◽  
Anna Krześlak
Keyword(s):  
Glucose Metabolism ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Metabolic Adaptation ◽  
Drug Bioavailability ◽  
Altered Glucose ◽  
The Warburg Effect

In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.

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

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.

scholarly journals Clinical Targeting of Altered Metabolism in High-Grade Glioma

2021 ◽  
Vol 27 (5) ◽  
pp. 386-394
Author(s):  
Andrew J. Scott ◽  
Costas A. Lyssiotis ◽  
Daniel R. Wahl
Keyword(s):  
High Grade Glioma ◽  
High Grade ◽  
Altered Metabolism

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

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.

scholarly journals Slow TCA flux implies low ATP production in tumors

2021 ◽  
Author(s):  
Caroline R. Bartman ◽  
Yihui Shen ◽  
Won Dong Lee ◽  
Tara TeSlaa ◽  
Connor S.R. Jankowski ◽  
...  
Keyword(s):  
Electron Transport ◽  
Warburg Effect ◽  
Electron Transport Chain ◽  
Aerobic Glycolysis ◽  
Tca Cycle ◽  
High Energy ◽  
Glycolytic Flux ◽  
Atp Production ◽  
Transport Chain ◽  
The Warburg Effect

SummaryThe tricarboxylic acid (TCA) cycle oxidizes carbon substrates to carbon dioxide, with the resulting high energy electrons fed into the electron transport chain to produce ATP by oxidative phosphorylation. Healthy tissues derive most of their ATP from oxidative metabolism, and the remainder from glycolysis. The corresponding balance in tumors remains unclear. Tumors upregulate aerobic glycolysis (the Warburg effect), yet they also typically require an intact TCA cycle and electron transport chain1–6. Recent studies have measured which nutrients contribute carbon to the tumor TCA metabolites7,8, but not tumor TCA flux: how fast the cycle turns. Here, we develop and validate an in vivo dynamic isotope tracing-mass spectrometry strategy for TCA flux quantitation, which we apply to all major mouse organs and to five tumor models. We show that, compared to the tissue of origin, tumor TCA flux is markedly suppressed. Complementary glycolytic flux measurements confirm tumor glycolysis acceleration, but the majority of tumor ATP is nevertheless made aerobically, and total tumor ATP production is suppressed compared to healthy tissues. In murine pancreatic cancer, this is accommodated by downregulation of the major energy-using pathway in the healthy exocrine pancreas, protein synthesis. Thus, instead of being hypermetabolic as commonly assumed, tumors apparently make ATP at a lower than normal rate. We propose that, as cells de-differentiate into cancer, they eschew ATP-intensive processes characteristic of the host tissue, and that the resulting suppressed ATP demand contributes to the Warburg effect and facilitates cancer growth in the nutrient-poor tumor microenvironment.

scholarly journals Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

2021 ◽  
Vol 22 (12) ◽  
pp. 6434
Author(s):  
Aldona Kasprzak
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Glucose Metabolism ◽  
Warburg Effect ◽  
Mapk Signaling ◽  
Colorectal Carcinogenesis ◽  
Insulin Like Growth Factor ◽  
Aberrant Expression ◽  
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.

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

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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