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IUBMB Life Jul 2023Cervical cancer is one of the most common female malignant tumors, with typical cancer metabolism characteristics of increased glycolysis flux and lactate accumulation....
Cervical cancer is one of the most common female malignant tumors, with typical cancer metabolism characteristics of increased glycolysis flux and lactate accumulation. 2-Deoxy-D-glucose (2-DG) is a glycolysis inhibitor that acts on hexokinase, the first rate-limiting enzyme in the glycolysis pathway. In this research, we demonstrated that 2-DG effectively reduced glycolysis and impaired mitochondrial function in cervical cancer cell lines HeLa and SiHa. Cell function experiments revealed that 2-DG significantly inhibited cell growth, migration, and invasion, and induced G0/G1 phase arrest at non-cytotoxic concentrations. In addition, we found that 2-DG down-regulated Wingless-type (Wnt)/β-catenin signaling. Mechanistically, 2-DG accelerated the degradation of β-catenin protein, which resulted in the decrease of β-catenin expression in both nucleus and cytoplasm. The Wnt agonist lithium chloride and β-catenin overexpression vector could partially reverse the inhibition of malignant phenotype by 2-DG. These data suggested that 2-DG exerted its anti-cancer effects on cervical cancer by co-targeting glycolysis and Wnt/β-catenin signaling. As expected, the combination of 2-DG and Wnt inhibitor synergistically inhibited cell growth. It is noteworthy that, down-regulation of Wnt/β-catenin signaling also inhibited glycolysis, indicating a similar positive feedback regulation between glycolysis and Wnt/β-catenin signaling. In conclusion, we investigated the molecular mechanism by which 2-DG inhibits the progression of cervical cancer in vitro, elucidated the interregulation between glycolysis and Wnt/β-catenin signaling, and preliminarily explored the effect of combined targeting of glycolysis and Wnt/β-catenin signaling on cell proliferation, which provides more possibilities for the formulation of subsequent clinical treatment strategies.
Topics: Humans; Female; Uterine Cervical Neoplasms; beta Catenin; Cell Line, Tumor; Glucose; Wnt Signaling Pathway; Glycolysis; Deoxyglucose; Cell Proliferation; Cell Movement; Gene Expression Regulation, Neoplastic
PubMed: 36809563
DOI: 10.1002/iub.2706 -
Journal of Nuclear Cardiology :... Dec 2022
Topics: Humans; Fluorodeoxyglucose F18; Immunoglobulin G4-Related Disease; Positron-Emission Tomography
PubMed: 34964084
DOI: 10.1007/s12350-021-02887-1 -
Biochimie Apr 2022A characteristic of cancer cells is increased glucose uptake and glycolysis for energy production and hydroperoxide detoxification due to mitochondrial dysfunction....
A characteristic of cancer cells is increased glucose uptake and glycolysis for energy production and hydroperoxide detoxification due to mitochondrial dysfunction. Thus, inhibition of glucose uptake and glycolysis represent smart novel therapy. We used 2-deoxyglucose (2DG) as a glycolysis inhibitor and acarbose (ACA), a specific alpha-glucosidase inhibitor, to decrease glucose uptake. Mice bearing mammary adenocarcinoma tumors were treated by 2DG and/or ACA. Relative tumor volume, tumor growth inhibition rate, relative body weight, glucose concentration, hexokinase-1 protein level by ELISA, pyruvate, and ATP (glycolysis products), reactive oxygen species (ROS), total glutathione T-GSH, apoptosis, and histopathology were measured in treated and untreated groups. Our results showed that combination therapy inhibited tumor volume and increased tumor growth inhibition rate, body weight reduction, decreasing glucose level, HK-1 level, and inhibition of glycolysis products. In addition, combination therapy induced oxidative stress, increase ROS, and decrease T-GSH. Furthermore, immunohistochemistry examination showed the broader area of apoptosis in breast cancer treated by combination agents. In conclusion, our result revealed that the novel combination inhibits glycolysis and glucose uptake and induced oxidative stress and apoptosis.
Topics: Acarbose; Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Deoxyglucose; Female; Glucose; Glycolysis; Humans; Mice; Oxidative Stress
PubMed: 35066100
DOI: 10.1016/j.biochi.2022.01.007 -
Current Oncology Reports Jul 2020Molecular imaging with positron emission tomography (PET) is a powerful tool to visualize breast cancer characteristics. Nonetheless, implementation of PET imaging into... (Review)
Review
PURPOSE OF REVIEW
Molecular imaging with positron emission tomography (PET) is a powerful tool to visualize breast cancer characteristics. Nonetheless, implementation of PET imaging into cancer care is challenging, and essential steps have been outlined in the international "imaging biomarker roadmap." In this review, we identify hurdles and provide recommendations for implementation of PET biomarkers in breast cancer care, focusing on the PET tracers 2-[F]-fluoro-2-deoxyglucose ([F]-FDG), sodium [F]-fluoride ([F]-NaF), 16α-[F]-fluoroestradiol ([F]-FES), and [Zr]-trastuzumab.
RECENT FINDINGS
Technical validity of [F]-FDG, [F]-NaF, and [F]-FES is established and supported by international guidelines. However, support for clinical validity and utility is still pending for these PET tracers in breast cancer, due to variable endpoints and procedures in clinical studies. Assessment of clinical validity and utility is essential towards implementation; however, these steps are still lacking for PET biomarkers in breast cancer. This could be solved by adding PET biomarkers to randomized trials, development of imaging data warehouses, and harmonization of endpoints and procedures.
Topics: Biomarkers; Breast Neoplasms; Female; Fluorodeoxyglucose F18; Humans; Molecular Imaging; Positron Emission Tomography Computed Tomography
PubMed: 32627087
DOI: 10.1007/s11912-020-00940-9 -
Journal of Nuclear Cardiology :... Apr 2022
Topics: Fluorodeoxyglucose F18; Humans; Multimodal Imaging; Positron-Emission Tomography
PubMed: 32737840
DOI: 10.1007/s12350-020-02302-1 -
Biochemical Pharmacology Dec 2020Most malignant cells display increased glucose absorption and metabolism compared to surrounding tissues. This well-described phenomenon results from a metabolic... (Review)
Review
Most malignant cells display increased glucose absorption and metabolism compared to surrounding tissues. This well-described phenomenon results from a metabolic reprogramming occurring during transformation, that provides the building blocks and supports the high energetic cost of proliferation by increasing glycolysis. These features led to the idea that drugs targeting glycolysis might prove efficient in the context of cancer treatment. One of these drugs, 2-deoxyglucose (2-DG), is a synthetic glucose analog that can be imported into cells and interfere with glycolysis and ATP generation. Its preferential targeting to sites of cell proliferation is supported by the observation that a derived molecule, 2-fluoro-2-deoxyglucose (FDG) accumulates in tumors and is used for cancer imaging. Here, we review the toxicity mechanisms of this drug, from the early-described effects on glycolysis to its other cellular consequences, including inhibition of protein glycosylation and endoplasmic reticulum stress, and its interference with signaling pathways. Then, we summarize the current data on the use of 2-DG as an anti-cancer agent, especially in the context of combination therapies, as novel 2-DG-derived drugs are being developed. We also show how the use of 2-DG helped to decipher glucose-signaling pathways in yeast and favored their engineering for biotechnologies. Finally, we discuss the resistance strategies to this inhibitor that have been identified in the course of these studies and which may have important implications regarding a medical use of this drug.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Clinical Trials as Topic; Deoxyglucose; Drug Resistance, Neoplasm; Glucose; Glycolysis; Humans
PubMed: 32890467
DOI: 10.1016/j.bcp.2020.114213 -
Molecular Metabolism Jun 2023Cancer cells use glycolysis for generation of metabolic intermediates and ATP needed for cell growth and proliferation. The transcription factor C/EBPβ-LIP stimulates...
OBJECTIVE
Cancer cells use glycolysis for generation of metabolic intermediates and ATP needed for cell growth and proliferation. The transcription factor C/EBPβ-LIP stimulates glycolysis and mitochondrial respiration in cancer cells. We initially observed that high expression of C/EBPβ-LIP makes cells vulnerable to treatment with the glycolysis inhibitor 2-deoxyglucose. The aim of the study was to uncover the involved mechanisms of C/EBPβ-LIP induced sensitivity to glycolysis inhibition.
METHODS
We used genetically engineered cell lines to examine the effect of C/EBPβ-LIP and -LAP protein isoforms on glycolysis and NADH/NAD metabolism in mouse embryonic fibroblasts (MEFs), and triple negative breast cancer (TNBC) cells that endogenously express high levels of C/EBPβ-LIP. Analyses included assays of cell proliferation, cell survival and metabolic flux (OCR and ECAR by Seahorse XF96). Small molecule inhibitors were used to identify underlying metabolic pathways that mediate sensitivity to glycolysis inhibition induced by C/EBPβ-LIP.
RESULTS
The transcription factor C/EBPβ-LIP stimulates both glycolysis and the malate-aspartate shuttle (MAS) and increases the sensitivity to glycolysis inhibition (2-deoxyglucose) in fibroblasts and breast cancer cells. Inhibition of glycolysis with ongoing C/EBPβ-LIP-induced MAS activity results in NADH depletion and apoptosis that can be rescued by inhibiting either the MAS or other NAD-regenerating processes.
CONCLUSION
This study indicates that a low NADH/NAD+ ratio is an essential mediator of 2-deoxyglucose toxicity in cells with high cytoplasmic NAD-regeneration capacity and that simultaneous inhibition of glycolysis and lowering of the NADH/NAD ratio may be considered to treat cancer.
Topics: Animals; Mice; CCAAT-Enhancer-Binding Protein-beta; Aspartic Acid; Malates; NAD; Fibroblasts; Glycolysis; Deoxyglucose
PubMed: 37062524
DOI: 10.1016/j.molmet.2023.101726 -
Clinical Lymphoma, Myeloma & Leukemia Jul 2020The aim of this systematic review was to examine published data about the potential role of Fluorine-18-fluorodeoxyglucose positron emission tomography or positron... (Review)
Review
The aim of this systematic review was to examine published data about the potential role of Fluorine-18-fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography (F-FDG PET or PET/CT) in patients affected by mantle cell lymphoma (MCL). A comprehensive computer literature search of Scopus, PubMed/MEDLINE, and Embase databases was conducted, including articles indexed up to November, 2019; 25 studies or subsets in studies analyzing the value of F-FDG PET or PET/CT in patients with MCL were eligible for inclusion. From the analyses of the selected studies, the following main findings are described: (1) MCL are F-FDG-avid in most of cases, especially nodal lesions, but bone marrow and gastrointestinal disease localizations have low F-FDG avidity; (2) F-FDG PET/CT seems to be helpful in staging setting, showing a better diagnostic performance than conventional imaging and a positive impact on clinical stage; (3) F-FDG PET/CT is useful in evaluating treatment response, especially after chemotherapy and transplantation; and (4) metabolic response after therapy seems to have a prognostic role. Despite several limitations affecting this analysis, especially related to the heterogeneity of the studies included, MCL is an F-FDG-avid lymphoma in most of the cases, with the exception of bone marrow and gastrointestinal disease. Moreover, F-FDG PET/CT seems to be useful in evaluating treatment response and prognosis.
Topics: Female; Fluorodeoxyglucose F18; Humans; Lymphoma, Mantle-Cell; Male; Nuclear Medicine; Positron Emission Tomography Computed Tomography
PubMed: 32169480
DOI: 10.1016/j.clml.2020.01.018 -
Current Protein & Peptide Science 2020Skeletal muscle is the largest organ in the body and constitutes almost 40% of body mass. It is also the primary site of insulin-mediated glucose uptake, and skeletal... (Review)
Review
Skeletal muscle is the largest organ in the body and constitutes almost 40% of body mass. It is also the primary site of insulin-mediated glucose uptake, and skeletal muscle insulin resistance, that is, diminished response to insulin, is characteristic of Type 2 diabetes (T2DM). One of the foremost reasons posited to explain the etiology of T2DM involves the modification of proteins by dicarbonyl stress due to an unbalanced metabolism and accumulations of dicarbonyl metabolites. The elevated concentration of dicarbonyl metabolites (i.e., glyoxal, methylglyoxal, 3-deoxyglucosone) leads to DNA and protein modifications, causing cell/tissue dysfunctions in several metabolic diseases such as T2DM and other age-associated diseases. In this review, we recapitulated reported effects of dicarbonyl stress on skeletal muscle and associated extracellular proteins with emphasis on the impact of T2DM on skeletal muscle and provided a brief introduction to the prevention/inhibition of dicarbonyl stress.
Topics: Deoxyglucose; Diabetes Mellitus, Type 2; Extracellular Matrix Proteins; Gene Expression Regulation; Glycation End Products, Advanced; Glyoxal; Humans; Insulin; Insulin Resistance; Isoenzymes; Lactoylglutathione Lyase; Muscle, Skeletal; Oxidative Stress; Protein Carbonylation; Pyruvaldehyde; Signal Transduction
PubMed: 31746292
DOI: 10.2174/1389203720666191119100759 -
Journal of Nuclear Cardiology :... Aug 2022
Topics: Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography
PubMed: 34935109
DOI: 10.1007/s12350-021-02881-7