Activation Of Aerobic Glycolysis Research Articles

Abstract 3063: Defining oncogene-specific metabolic vulnerabilities in a mouse model of hepatocellular carcinoma

Abstract Despite the continued success of advanced cancer therapies, hepatocellular carcinoma (HCC) represents a substantial challenge to current treatment modalities that are not sufficiently effective for the management of advanced disease. Metabolic reprogramming is a hallmark of cancer and many oncogenic signaling pathways impact on cellular metabolism. Here, we are investigating changes in metabolism in different oncogene-driven mouse models of liver cancer to identify selective metabolic vulnerabilities associated with HCC that could be implicated in tumor initiation and progression to be exploited for cancer therapy. Transposon-based vectors coding for different combinations of oncogenes, either Myc and Akt1Myr (CaMIA) or Myc and NrasG12V (CaMIN), were transduced by hydrodynamic tail vein injected into C57BL/6 mice. The resulting liver tumors and control livers were subjected to a comprehensive profiling of polar metabolites (metabolomics) and lipids (lipidomics and total fatty acids) as well as changes in gene expression (transcriptomics). Despite similar overall survival, the two models display marked differences in the presentation of the tumors, with CaMIA showing larger aggressive tumors, while CaMIN livers contain numerous small tumor nodules. Both models also showed evidence for the deregulation of intermediate metabolism, indicating activation of aerobic glycolysis and deregulation of glutamine metabolism. Lipidomic analysis revealed substantial lipidome remodeling in both models. Oncogene-specific alterations included elevated levels of lysophosphatidylcholine (LPC) in CaMIN tumors, while CaMIA tumors displayed high levels of ether phospholipids compared to CaMIN and normal liver. Moreover, the fraction of polyunsaturated fatty acids (PUFAs) was enhanced in lipids from CaMIN tumors, while monounsaturated fatty acids (MUFAs) were enriched in CaMIA tumors. Furthermore, tumors from both genotypes produced higher levels of oxylipins, a class of lipid mediators involved in signaling and inflammation, compared to normal liver. Transcriptome analysis confirmed these metabolic alterations and revealed evidence for enhanced inflammatory signaling in CaMIN. In addition, analysis of tumor microenvironment composition disclosed specific differences in stromal components, indicative of immune evasion through checkpoint activation. Experiments in primary murine liver cancer cell lines confirmed oncogene-specific metabolic rearrangements and suggest elevated sensitivity towards inhibitors of lipid remodeling. Future experiments will investigate the role of altered lipid metabolism in tumor development and immune evasion in liver cancer. Citation Format: Kamal Al-Shami, Marteinn Snaebjornsson, Felix Vogel, Lisa Schlicker, Phillip Pöller, Daniel Dauch, Almut Schulze. Defining oncogene-specific metabolic vulnerabilities in a mouse model of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3063.

PHLPP1 inhibits the growth and aerobic glycolysis activity of human ovarian granular cells through inactivating AKT pathway

BackgroundPolycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features, and PCOS is associated with infertility. PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) has been shown to regulate AKT. The aim of present study is to investigate the role of PHLPP1 in PCOS.MethodsThe expression levels of PHLPP1 in dihydrotestosterone (DHT)-treated human ovarian granular KGN cells were determined by qRT-PCR and Western blot. PHLPP1 was silenced or overexpressed using lentivirus. Cell proliferation was detected by CCK-8. Apoptosis and ROS generation were analyzed by flow cytometry. Glycolysis was analyzed by measuring extracellular acidification rate (ECAR).ResultsDHT treatment suppressed proliferation, promoted apoptosis, enhanced ROS, and inhibited glycolysis in KGN cells. PHLPP1 silencing alleviated the DHT-induced suppression of proliferation and glycolysis, and promotion of apoptosis and ROS in KGN cells. PHLPP1 regulated cell proliferation and glycolysis in human KGN cells via the AKT signaling pathway.ConclusionsOur results showed that PHLPP1 mediates the proliferation and aerobic glycolysis activity of human ovarian granular cells through regulating AKT signaling.

Сell clusters isolation in glioblastomas and their functional and molecular characterization using new morphometric approaches

BackgroundDigital pathology has come a long way in terms of creating tools to improve existing diagnostic approaches. However, several pathology fields, such as neuropathology, are still characterized by low coverage from machine learning tools and neural network analysis, which may be due to the complexity of the internal cellular and molecular structure of the corresponding neoplasms, including glioblastomas. MethodIn the framework of this study, using advanced proprietary tools for obtaining images of histological slides and their deep morphometric analysis, we studied samples of 198 patients with glioblastoma with the selection of morphometric cell clusters. Also, cells of each cluster were isolated, and their proliferative, migratory, invasive activity, survival ability, aerobic glycolysis activity, and chemo- and radioresistance were studied. ResultsFour morphometric clusters were identified, including small-cell cluster, paracirculonuclear cluster, hypochromic cluster, and macronuclear cluster, which significantly differed in morphometric parameters and functional parameters. Hypochromic cluster cells demonstrated the highest proliferation activity; macronuclear cluster was the most active glucose consumer; paracirculonuclear cluster had the most prominent migratory and invasive activity and hypoxia resistance; small-cell cluster demonstrated predominantly average values of all parameters. Moreover, additional analysis revealed the presence of a separate subcluster of stem cell elements that correspond in their molecular properties to glioma stem cells and are present in all four clusters. It also turned out that several key molecular parameters of glioblastoma, such as mutational modifications in the EGFR, PDGFRA, and NF1 genes, along with the molecular GBM subtype, are significantly correlated with the identified cell clusters. ConclusionsThus, the results represent an up-and-coming innovation in the practical field of digital pathology and fundamental questions of glioma carcinogenesis.

Metabolic changes during larval-pupal metamorphosis of Helicoverpa armigera.

Energy metabolism is essential for insect metamorphosis. The accumulation and utilization of energy is still not completely clear during larval-pupal metamorphosis of holometabolous insects. We used metabolome and transcriptome analysis to reveal key metabolic changes in the fat body and plasma and the underlying metabolic regulation mechanism of Helicoverpa armigera, an important global agricultural insect pest, during larval-pupal metamorphosis. During the feeding stage, activation of aerobic glycolysis provided intermediate metabolites and energy for cell proliferation and lipid synthesis. During the non-feeding stages (the initiation of the wandering stage and the prepupal stage), aerobic glycolysis was suppressed, while, triglyceride degradation was activated in the fat body. The blocking of metabolic pathways in the fat body was probably caused by 20-hydroxyecdysone-induced cell apoptosis. 20-hydroxyecdysone cooperated with carnitine to promote the degradation of triglycerides and the accumulation of acylcarnitines in the hemolymph, allowing rapid transportation and supply of lipids from the fat body to other organs, which provided a valuable reference for revealing the metabolic regulation mechanism of lepidopteran larvae during the last instar. Carnitine and acylcarnitines are first reported to be key factors that mediate the degradation and utilization of lipids during larval-pupal metamorphosis of lepidopteran insects.

Profiling of metabolites, proteins, and protein phosphorylation in silica-exposed BEAS-2B epithelial cells.

Silicosis is an uncurable occupational disease induced by crystalline silica. Increased prevalence of silicosis has resulted in the increased need for development of treatment options. Although macrophages respond first to silica, epithelial cells are also involved in silicosis. However, changes in protein and metabolite levels have not been reported simultaneously. We used mass spectrometry to profile changes in metabolites, proteins, and phosphorylation in silica-exposed BEAS-2B epithelial cells. Silica exposure increased TCA cycle, alanine, aspartate and glutamate metabolism, and aerobic glycolysis activity. In addition, protein levels in the endoplasmic reticulum were significantly altered, and phosphorylation of MAPK signaling proteins was increased. The results of this study increased understanding the role of epithelial cells in silicosis.

THE ROLE OF NUTRITIONAL RESTRICTION IN THE PATHOGENESIS OF MALIGNANT TUMORS

Cancer is one of the leading causes of death in developed countries. Cancer incidence is growing, and it may be associated with longer life expectancy that leads to higher risk of cancer development. Metabolic changes are among the most important aspects of the tumor progression, which appear both in the tumor cells themselves and in the tumor microenvironment, affecting later the entire organism as a whole. Abnormal metabolism of tumor cells, including activation of aerobic glycolysis and enhancement of anabolic pathways, is important in metastasizing, medical drug resistance, and in the implementation of tumor stem cell viability programs.

Homeobox A3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression.

Alterations in transcriptional regulators of glycolytic metabolism have been implicated in brain tumor growth, but the underlying molecular mechanisms remain poorly understood. Knockdown and overexpression cells were used to explore the functional roles of HOXA3 in cell proliferation, tumor formation, and aerobic glycolysis. Chromatin immunoprecipitation, luciferase assays, and western blotting were performed to verify the regulation of HK2 and PKM2 by HOXA3. PLA, Immunoprecipitation, and GST-pull-down assays were used to examine the interaction of HOXA3 and KDM6A. We report that transcription factor homeobox A3 (HOXA3), which is aberrantly highly expressed in glioblastoma (GBM) patients and predicts poor prognosis, transcriptionally activates aerobic glycolysis, leading to a significant acceleration in cell proliferation and tumor growth. Mechanically, we identified KDM6A, a lysine-specific demethylase, as an important cooperator of HOXA3 in regulating aerobic glycolysis. HOXA3 activates KDM6A transcription and recruits KDM6A to genomic binding sites of glycolytic genes, targeting glycolytic genes for transcriptional activation by removing the suppressive histone modification H3K27 trimethylation. Further evidence demonstrates that HOXA3 requires KDM6A for transcriptional activation of aerobic glycolysis and brain tumor growth. Our findings provide a novel molecular mechanism linking HOXA3-mediated transactivation and KDM6A-coupled H3K27 demethylation in regulating glucose metabolism and GBM progression.

Exosomes derived from the blood of patients with sepsis regulate apoptosis and aerobic glycolysis in human myocardial cells via the hsa‑miR‑1262/SLC2A1 signaling pathway.

Myocardial injury occurs in the majority of patients with sepsis and is associated with early mortality. MicroRNAs (miRs) transported by exosomes have been implicated in numerous diseases, such as tumors, acute myocardial infarction and cardiovascular disease. Human serum albumin (hsa)‑miR‑1262 has been shown to serve a role in sepsis; however, its role in exosomes isolated from patients with sepsis and septic myocardial injury remains unclear. In the present study, serum exosomes were isolated via ultracentrifugation. Solute carrier family2 member1 (SLC2A1), an essential mediator in energy metabolism, was silenced and overexpressed in the human myocardial AC16 cell line using lentiviral plasmids containing either SLC2A1‑targeting short interfering RNAs or SLC2A1 cDNA, respectively. Cell apoptosis was analyzed using flow cytometry, and the extracellular acidification rate and oxygen consumption rate of AC16 cells were determined using an XFe24 Extracellular Flux Analyzer. Furthermore, the dual‑luciferase reporter assay was used to evaluate the interaction between hsa‑miR‑1262 and SLC2A1. Finally, reverse transcription‑quantitative PCR and western blotting were used to evaluate gene and protein expression levels, respectively. Exosomes isolated from the blood of patients with sepsis (Sepsis‑exo) markedly reduced aerobic glycolysis activity, but significantly promoted the apoptosis of human AC16 cells in a time‑dependent manner. Moreover, Sepsis‑exo significantly increased hsa‑miR‑1262 expression levels, but significantly decreased SLC2A1 mRNA expression levels in a time‑dependent manner. Bioinformatics analysis indicated that hsa‑miR‑1262 bound to the 3'untranslated region of SLC2A1 to negatively regulate its expression. The silencing of SLC2A1 promoted apoptosis and suppressed glycolysis in AC16 cells, whereas SLC2A1 overexpression resulted in the opposite effects. Therefore, the present study demonstrated that exosomes derived from patients with sepsis may inhibit glycolysis and promote the apoptosis of human myocardial cells through exosomal hsa‑miR‑1262 via its target SLC2A1. These findings highlighted the importance of the hsa‑miR‑1262/SLC2A1 signaling pathway in septic myocardial injury and provided novel insights into therapeutic strategies for septic myocardial depression.

New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway.

Two series of novel amino acid Schiff base ligands containing heterocyclic moieties, such as quinazolinone 3–11 and indole 12–20 were successfully synthesized and confirmed by spectroscopic techniques and elemental analysis. Furthermore, all compounds were investigated in silico for their ability to inhibit mitochondrial NADH: ubiquinone oxidoreductase (complex I) by targeting the AMPK/mTOR signaling pathway and inhibiting hexokinase, a key glycolytic enzyme to prevent the Warburg effect in cancer cells. This inhibitory pathway may be an effective strategy to cause cancer cell death due to an insufficient amount of ATP. Our results revealed that, out of 18 compounds, two (11 and 20) were top-ranked as they exhibited the highest binding energies of −8.8, −13.0, −7.9, and −10.0 kcal/mol in the docking analysis, so they were then selected for in vitro assessment. Compound 11 promoted the best cytotoxic effect on MCF-7 with IC50 = 64.05 ± 0.14 μg/mL (0.135 mM) while compound 20 exhibited the best cytotoxic effect on MDA-231 with IC50 = 46.29 ± 0.09 μg/mL (0.166 mM) Compounds 11 and 20 showed significant activation of AMPK protein and oxidative stress, which led to elevated expression of p53 and Bax, reduced Bcl-2 expression, and caused cell cycle arrest at the sub-G0/G1 phase. Moreover, compounds 11 and 20 showed significant inhibition of the mTOR protein, which led to the activation of aerobic glycolysis for survival. This alternative pathway was also blocked as compounds 11 and 20 showed significant inhibitory effects on the hexokinase enzyme. These findings demonstrate that compounds 11 and 20 obeyed Lipinski’s rule of five and could be used as privileged scaffolds for cancer therapy via their potential inhibition of mitochondrial complex I-associated hexokinase.

Development of an Aerobic Glycolysis Index for Predicting the Sorafenib Sensitivity and Prognosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a deadly tumor with high heterogeneity. Aerobic glycolysis is a common indicator of tumor growth and plays a key role in tumorigenesis. Heterogeneity in distinct metabolic pathways can be used to stratify HCC into clinically relevant subgroups, but these have not yet been well-established. In this study, we constructed a model called aerobic glycolysis index (AGI) as a marker of aerobic glycolysis using genomic data of hepatocellular carcinoma from The Cancer Genome Atlas (TCGA) project. Our results showed that this parameter inferred enhanced aerobic glycolysis activity in tumor tissues. Furthermore, high AGI is associated with poor tumor differentiation and advanced stages and could predict poor prognosis including reduced overall survival and disease-free survival. More importantly, the AGI could accurately predict tumor sensitivity to Sorafenib therapy. Therefore, the AGI may be a promising biomarker that can accurately stratify patients and improve their treatment efficacy.

2-Methoxy-1,4-Naphthoquinone (MNQ) Inhibits Glucose Uptake and Lactate Production in Triple-Negative Breast Cancer Cells

The persistent activation of aerobic glycolysis in cancer cells results in accumulation of lactate and other metabolic intermediates that contribute to tumorigenesis. Increased glycolysis is frequently dysregulated in triple-negative breast cancer (TNBC), which promotes tumor growth and immune escape. This study was conducted to investigate the effect of 2-methoxy-1, 4-naphthoquinone (MNQ), compound extracted from Impatiens balsamina on glycolytic activities in human breast adenocarcinoma, MDA-MB-231 cells. Initially, MTT proliferation assay was used to test the cell viability with various doses of MNQ (5-100 µM). As the half maximal inhibitory concentration (IC50) was obtained, glucose uptake and lactate assays of the cells were tested with IC50 dose of MNQ. The treated cells were also subjected to gene and protein analysis of glycolysis-related molecules (GLUT1 and Akt). The results showed that MNQ decreased the percentage of MDA-MB-231 cell viability in a dose-dependent manner with the IC50 value of 29 µM. The percentage of glucose uptake into the cells and lactate production decreased significantly after treatment with MNQ as compared to untreated cells. Remarkably, the expressions of GLUT1 and Akt molecules decreased in MNQ-treated cells, suggesting that the inhibition of glycolysis by MNQ is GLUT1-dependent and possibly mediated by the Akt signaling pathway. Our findings indicate the ability of MNQ to inhibit the glycolytic activities as well as glycolysis-related molecules in MDA-MB-231 cells, suggesting the potential of MNQ to be further developed as an effective anticancer agent against TNBC cells.

Bidirectional astrocytic GLUT1 activation by elevated extracellular K+

The acute rise in interstitial K+ that accompanies neural activity couples the energy demand of neurons to the metabolism of astrocytes. The effects of elevated K+ on astrocytes include activation of aerobic glycolysis, inhibition of mitochondrial respiration and the release of lactate. Using a genetically encoded FRET glucose sensor and a novel protocol based on 3-O-methylglucose trans-acceleration and numerical simulation of glucose dynamics, we report that extracellular K+ is also a potent and reversible modulator of the astrocytic glucose transporter GLUT1. In cultured mouse astrocytes, the stimulatory effect developed within seconds, engaged both the influx and efflux modes of the transporter, and was detected even at 1 mM incremental K+ . The modulation of GLUT1 explains how astrocytes are able to maintain their glucose pool in the face of strong glycolysis stimulation. We propose that the stimulation of GLUT1 by K+ supports the production of lactate by astrocytes and the timely delivery of glucose to active neurons.

Abstract 4097: Enhanced synergistic efficacy of simvastatin and metformin on enzalutamide resistant prostate cancer cells

Abstract Androgen deprivation therapy (ADT) continues to be the mainstay therapy for advance-stage prostate cancer. Although malignant cells respond to ADT initially, subsequently colonize and re-emerge as castration-resistant prostate cancer (CRPC). Enzalutamide (ENZU), a second-generation AR antagonist exhibits survival advantage in CRPC patients, however, ~30% of patients develop resistance after ENZU treatment, activating AR in these tumors. These ENZU-resistant tumors poorly respond to chemotherapy and other treatment modalities. Therefore, identification of an effective low-cost therapeutic alternative with fewer side effects may lead to increased survival and greatly benefit the quality-of-life of these patients. Activation of aerobic glycolysis and biomass production is implicated, in part, to be responsible for CRPC cells to acquire androgen resistance. Previous studies from our laboratory have demonstrated that synergistic combination of simvastatin (SIM), a drug for the treatment of hypercholesterolemia and metformin (MET), a glucose-lowering drug inhibits CRPC growth, invasiveness and migration with minimal effect on normal prostate epithelial cells (Mol Cancer Ther. 13(10):2288-2302, 2014). Here we examine whether the combination of SIM and MET could be effective in the treatment of ENZU-resistant prostate cancer cells. Human CRPC cells viz. C4-2B and its variant C4-2B-ENZU (C4-2B enzalutamide resistant) and 22Rv1 were used for the experiments. C4-2B-ENZU cells were generated by growing C4-2B cells in 20µM ENZU over 6 months and maintained in 5µM ENZU in the cell culture medium. 22Rv1 cells were inherently resistant to ENZU treatment. Both cells were treated with SIM (4µM) and MET (2mM) individually and in combination, followed by the assessment of cell viability, crystal violet assay, cell cycle analysis, migration, invasion, and expression of various target genes by Western blotting. C4-2B-ENZU and 22Rv1 cells were treated with a combination of SIM and MET at pharmacological dose range (500nM-4µM SIM and 250µM-2mM MET). Combination treatment with 4μM SIM and 2mM MET (SIM+MET) led to significant and synergistic inhibition of cell viability, migration, invasion and cell cycle blockade in both cancer cell lines. The individual treatments of SIM and MET exhibited little or no effect on these cells. Furthermore, SIM+MET combination decreased the expression of AR, AR-V7, p-Akt (Ser473), p-AMPKα1/α2 (Ser-485/491) and simultaneously increased p-AMPKα1 (Thr-172) and AMPKα kinase activity in these cells. We demonstrate, for the first time, that synergistic combination of SIM and MET may be an effective regimen for treatment ENZU-resistant prostate cancer cells. Citation Format: Eswar Shankar, Pingfu Fu, Gregory T. MacLennan, Sanjay Gupta. Enhanced synergistic efficacy of simvastatin and metformin on enzalutamide resistant prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4097.

Caveolin-1 inhibits breast cancer stem cells via c-Myc-mediated metabolic reprogramming

Breast cancer stem cells (BCSCs) are considered to be the root of breast cancer occurrence and progression. However, the characteristics and regulatory mechanisms of BCSCs metabolism have been poorly revealed, which hinders the development of metabolism-targeted treatment strategies for BCSCs elimination. Herein, we demonstrated that the downregulation of Caveolin-1 (Cav-1) usually occurred in BCSCs and was associated with a metabolic switch from mitochondrial respiration to aerobic glycolysis. Meanwhile, Cav-1 could inhibit the self-renewal capacity and aerobic glycolysis activity of BCSCs. Furthermore, Cav-1 loss was associated with accelerated mammary-ductal hyperplasia and mammary-tumor formation in transgenic mice, which was accompanied by enrichment and enhanced aerobic glycolysis activity of BCSCs. Mechanistically, Cav-1 could promote Von Hippel-Lindau (VHL)-mediated ubiquitination and degradation of c-Myc in BCSCs through the proteasome pathway. Notably, epithelial Cav-1 expression significantly correlated with a better overall survival and delayed onset age of breast cancer patients. Together, our work uncovers the characteristics and regulatory mechanisms of BCSCs metabolism and highlights Cav-1-targeted treatments as a promising strategy for BCSCs elimination.

HIF-1α as a central mediator of cellular resistance to intracellular pathogens.

Hypoxia-inducible transcription factor-1α (HIF-1α) was originally identified as a master regulator of cellular responses to hypoxia. More recently, HIF-1α has emerged as a critical regulator of immune cell function that couples shifts in cellular metabolism to cell type-specific transcriptional outputs. Activation of macrophages with inflammatory stimuli leads to induction of the metabolic program aerobic glycolysis and to HIF-1α stabilization, which reinforce one another in a positive feedback loop that helps drive macrophage activation. This activation of aerobic glycolysis and HIF-1α is important both for production of inflammatory cytokines, such as IL-1β, and for cell intrinsic control of infection. Here, we review the importance of HIF-1α for control of bacterial, fungal, and protozoan intracellular pathogens, highlighting recent findings that reveal mechanisms by which HIF-1α is activated during infection and how HIF-1α coordinates antimicrobial responses of macrophages.

Metabolomic profiling highlights the metabolic bases of acute-on-chronic and post-hepatectomy liver failure

BackgroundPosthepatectomy liver failure (PHLF) is the main limitation to extending liver resection but its pathophysiology is not yet fully understood. The aim of the study was to describe the metabolic adaptations that occur with PHLF. MethodsA retrospective study of 82 patients using nuclear magnetic resonance metabolomics to identify and quantify intra-hepatic metabolites was performed. The metabolite levels were compared using metabolic network analysis ADEMA between fatal PHLF (FLF) and non fatal PHLF and according to PHLF/ACLF grading. ResultsMetabolomic profiles were significantly different between patients presenting FLF and non FLF or grade 3 ACLF versus < grade 3 ACLF. In the patients undergoing hepatectomy, valine, alanine and glycerophosphocholine were identified as powerful biomarkers to predict FLF (AUROC 0.806, 0.802 and 0.856 respectively). Network analysis showed an activation of aerobic glycolysis with glutaminolysis as observed in highly proliferating systems. Inversely, ACLF3 showed deprivation of glucose and lactate compared to lower ACLF grade. ConclusionClinical andbiological severity of ACLF and PHLF correlate with specific metabolic adaptations. Metabolomics can predict fatal liver failure after hepatectomy and underline significant differences in the metabolic patterns of ACLF and PHLF.

Betulinic acid suppresses breast cancer aerobic glycolysis via caveolin-1/NF-κB/c-Myc pathway

Emerging evidence has suggested that targeting glycolysis may be a promising strategy for cancer treatment. Betulinic acid (BA) is a natural pentacyclic terpene that has been reported to be active in inhibiting various malignancies. Here, we showed that BA could inhibit aerobic glycolysis activity in breast cancer cell lines MCF-7 and MDA-MB-231 by hampering lactate production, glucose uptake and extracellular acidification rate (ECAR), as well as suppressing aerobic glycolysis-related proteins including c-Myc, lactate dehydrogenase A (LDH-A) and p-PDK1/PDK1 (pyruvate dehydrogenase kinase 1). Mechanistic studies validated Caveolin-1 (Cav-1) as one of key targets of BA in suppressing aerobic glycolysis, as BA administration resulted in Cav-1 upregulation, whereas silencing Cav-1 abrogated the inhibitory effect of BA on aerobic glycolysis. Further investigations demonstrated that BA suppressed aerobic glycolysis in breast cancer cells by regulating the Cav-1/NF-κB/c-Myc pathway. More meaningfully, BA significantly inhibited breast cancer growth and glycolytic activity in both the transgenic MMTV-PyVT+/− breast cancer spontaneous model and the zebrafish breast cancer xenotransplantation model without any detectable side effects in vivo. Taken together, our study sheds novel insights into BA as a promising candidate drug for suppressing aerobic glycolysis, highlighting Cav-1 as a potential molecular target of BA and aerobic glycolysis regulation.

Metabolic Therapy in hypertensive encephalopathy: emphasis on comorbidity of pathology

The development of primary and repeated disorders of cerebral circulation, vascular dementia, transient ischemic attacks, which are a consequence of the development of acute pathology in patients with hypertensive encephalopathy, lead to a state of persistent disability and disability. Today, the emphasis of treatment is placed on the important role of oxygen deficiency, which leads to the restriction of aerobic energy production due to disturbances in the energy-synthesizing function of the mitochondrial respiratory chain, depletion of endogenous antioxidant stores and activation of lipid peroxidation of cell membranes, leading to death of brain cells. By 2018, a large evidence base for the effectiveness of the use of metabolic therapy in neurology, which takes into account an important factor of the impact of comorbidity of the pathology. The effectiveness of antioxidant therapy in acute and chronic cerebrovascular diseases is confirmed by the fact that the antioxidant improves energy metabolism in the cell, and as a metabolite of the tricarboxylic acid cycle (succinate, which provides pronounced antioxidant and antihypoxic properties) has a positive effect on the main links of pathogenesis of diseases associated with processes freely Radical oxidation. It is proved that the preparation of Mexicor reduces the manifestation of oxidative stress, inhibits free radical peroxide oxidation of lipids, improves cellular energy metabolism, activates the energy-synthesizing functions of mitochondria, enhances compensatory activation of aerobic glycolysis and reduces the degree of inhibition of oxidative processes in the Krebs cycle. The drug Mexocor has a wide spectrum of pharmacological action, which allows it to be used successfully in acute and chronic cerebrovascular diseases, accompanied by vascular comorbidity.

Aerobic glycolysis activation through canonical WNT/β-catenin pathway in ALS

Energy is the major determinant of neuronal viability. We focus our synthesis on the hypothesis of the development of aerobic glycolysis by the stimulation of the canonical WNT/β-catenin pathway in amyotrophic lateral sclerosis (ALS). The stimulation of the canonical WNT/β-catenin pathway induces the activation of aerobic glycolysis, also called Warburg effect, via the stimulation of glycolytic enzymes such as Glut (glucose transporter), PKM2 (pyruvate kinase M2), PDK1 (pyruvate dehydrogenase kinase 1), LDH-A (lactate dehydrogenase A) and MCT-1 (monocarboxylate transporter 1). The aerobic glycolysis consists to a supply of a large part of glucose into lactate regardless of oxygen. Aerobic glycolysis is less efficient in terms of ATP production than oxidative phosphorylation due to the shunt of the TCA cycle. Dysregulation of cellular energy metabolism promotes cell death and participates to the progression of ALS. Controlling the expression of the canonical WNT/β-catenin signaling pathway is an attractive strategy to regulate aerobic glycolysis initiation and the progression of ALS.

Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity

Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis. However, the generalizability of such metabolic remodeling to other modes of M1 macrophage stimulation, e.g. type II interferons (IFNs) such as IFNγ, has remained unknown as has the functional significance of aerobic glycolysis during macrophage activation. Here we demonstrate that IFNγ induces a rapid activation of aerobic glycolysis followed by a reduction in oxidative phosphorylation in M1 macrophages. Elevated glycolytic flux sustains cell viability and inflammatory activity, while limiting reliance on mitochondrial oxidative metabolism. Adenosine triphosphate (ATP) distributed by aerobic glycolysis is critical for sustaining IFN-γ triggered JAK (Janus tyrosine kinase)-STAT-1 (Signal Transducer and Activator of Transcription 1) signaling with phosphorylation of the transcription factor STAT-1 as its signature trait. Inhibition of aerobic glycolysis not only blocks the M1 phenotype and pro-inflammatory cytokine/chemokine production in murine macrophages and also human monocytes/macrophages. These findings extend on the potential functional role of immuno-metabolism from LPS- to IFNγ-linked diseases such as atherosclerosis and autoimmune disease.