Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma

Journal of Experimental & Clinical Cancer Research, Год журнала: 2020, Номер 39(1)

Опубликована: Июль 6, 2020

Abstract Liver cancer has become the sixth most diagnosed and fourth leading cause of death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75–85% primary liver cancers, sorafenib first targeted drug advanced HCC treatment. However, resistance common because resultant enhancement aerobic glycolysis other molecular mechanisms. Aerobic was firstly found in HCC, acts as a hallmark regulation proliferation, immune evasion, invasion, metastasis, angiogenesis, HCC. The three rate-limiting enzymes glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), pyruvate kinases type M2 (PKM2) play an important role can be regulated by many mechanisms, such AMPK, PI3K/Akt HIF-1α, c-Myc noncoding RNAs. Because importance progression targeting key factors its pathway inhibition HK2, PFK or PKM2, represent potential new therapeutic approaches treatment

Язык: Английский

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Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways

Proceedings of the National Academy of Sciences, Год журнала: 2019, Номер 116(9), С. 3909 - 3918

Опубликована: Фев. 7, 2019

Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis metastasis. However, it is still largely unknown how orchestrate gene regulation balance OXPHOS activities. Previously, by modeling the of we have reported that can acquire a stable hybrid metabolic state in which both be used. Here, comprehensively characterize activity, establish theoretical framework coupling with pathways. Our results demonstrate direct association activities AMPK HIF-1, master regulators glycolysis, respectively, three major pathways: glucose oxidation, fatty acid oxidation. model further characterizes metabolically inactive where low activity OXPHOS. We verify prediction using metabolomics transcriptomics data from paired tumor adjacent benign tissue samples cohort breast patients RNA-sequencing The Cancer Genome Atlas. validate vitro studies aggressive triple-negative (TNBC) cells. experimental confirm TNBC maintain phenotype targeting necessary eliminate plasticity. In summary, our work serves as platform symmetrically study tuning modulates pathway vice versa.

Язык: Английский

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The Warburg effect and drug resistance

British Journal of Pharmacology, Год журнала: 2016, Номер 173(6), С. 970 - 979

Опубликована: Янв. 11, 2016

: The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This has been basis much speculation on survival advantage cells, tumourigenesis and microenvironment tumours. More recently, studies have begun to reveal how could influence drug efficacy our understanding energetics be exploited improve development. In particular, evidence is emerging demonstrating better modelling metabolic lead a prediction identification new combination strategies. review will provide details current complex interplay between glucose metabolism pharmacology discuss opportunities utilizing in future

Язык: Английский

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B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2

Cell Death and Disease, Год журнала: 2019, Номер 10(4)

Опубликована: Апрель 5, 2019

Accumulating evidence suggests that aerobic glycolysis is important for colorectal cancer (CRC) development. However, the underlying mechanisms have yet to be elucidated. B7-H3, an immunoregulatory protein, broadly overexpressed by multiple tumor types and plays a vital role in progression. In this study, we found overexpression of B7-H3 effectively increased rate glucose consumption lactate production, whereas knockdown had opposite effect. Furthermore, showed production promoting hexokinase 2 (HK2) expression CRC cells, also HK2 was key mediator B7-H3-induced chemoresistance. Depletion or treating cells with inhibitors could reverse increase B7-H3-endowed chemoresistance cells. Moreover, verified positive correlation between tissues patients. Collectively, our findings suggest may novel regulator metabolism via controlling result help develop as promising therapeutic target treatment.

Язык: Английский

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Chemoresistance and the Self-Maintaining Tumor Microenvironment

Cancers, Год журнала: 2018, Номер 10(12), С. 471 - 471

Опубликована: Ноя. 28, 2018

The progression of cancer is associated with alterations in the tumor microenvironment, including changes extracellular matrix (ECM) composition, rigidity, hypervascularization, hypoxia, and paracrine factors. One key malignant phenotype cells their ability to resist chemotherapeutics, elements ECM can promote chemoresistance through a variety signaling pathways, inducing gene expression protein activity that allow resistance. Furthermore, maintained as an environment facilitates chemoresistance, since its constitution modulates cancer-associated cells, which themselves affect microenvironment. In this review, we discuss how properties microenvironment interplay between these external stimuli. We focus on both response environment, well maintenance chemoresistant emerges from complex network present.

Язык: Английский

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Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Journal of Experimental & Clinical Cancer Research, Год журнала: 2020, Номер 39(1)

Опубликована: Янв. 30, 2020

Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) first line medicine for HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) cholesterol-lowering drug and reported inhibit growth. The present study aims determine whether Sora Sim co-treatment can improve resistance in HCC.The HCC cell LM3 established Sora-resistant (LM3-SR) were used the relationship between aerobic glycolysis. Cell proliferation, apoptosis glycolysis levels analyzed by western blotting, flow cytometry analysis biomedical tests. A xenograft model was also examine effect vivo. Detailed mechanistic studies undertaken use activators inhibitors, lentivirus transfections.Our results demonstrated that associated enhanced levels. Furthermore, LM3-SR cells more sensitive than cells, suggesting combined treatment both could enhance sensitivity Sora. This finding may be due suppression HIF-1α/PPAR-γ/PKM2 axis.Simvastatin axis, suppressing PKM2-mediated glycolysis, resulting decreased proliferation increased re-sensitizing

Язык: Английский

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Molecular Mechanisms of Chemoresistance Induced by Cisplatin in NSCLC Cancer Therapy

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(16), С. 8885 - 8885

Опубликована: Авг. 18, 2021

Cancer cells utilise several mechanisms to increase their survival and progression as well resistance anticancer therapy: deregulation of growth regulatory pathways by acquiring grow factor independence, immune system suppression, reducing the expression antigens activating T lymphocyte (mimicry), induction anti-apoptotic signals counter action drugs, activation DNA repair driving active efflux drugs from cell cytoplasm, epigenetic regulation microRNAs (miRNAs). Because it is commonly diagnosed late, lung cancer remains a major malignancy with low five-year rate; when diagnosed, often highly advanced, may have acquired drug resistance. This review summarises main involved in cisplatin interactions between cisplatin-resistant tumour microenvironment. It also analyses changes gene profile sensitive vs. non-small (NSCLC) cellular model using GSE108214 Gene Expression Omnibus database. describes protein-protein interaction network that indicates dysregulated TP53, MDM2, CDKN1A genes they encode top networking proteins be tolerance, these all being upregulated cells. Furthermore, illustrates multifactorial nature examining diversity present NSCLC based on KEGG pathway analysis.

Язык: Английский

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Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 27, 2024

Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The receptor ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical signaling transduction. Accumulating evidence indicates that the pathway serves as both an oncogenic factor a tumor suppressor various cancer types. Dysregulation of this promotes epithelial-mesenchymal transition angiogenesis malignancies, closely linked proliferation, invasion, metastasis. Furthermore, contributes maintaining stem-like properties cells, thereby enhancing invasiveness. regulatory metabolic reprogramming microenvironment suggests pivotal involvement balancing suppressive effects. Moreover, implicated conferring chemoresistance cells. Therefore, comprehensive understanding these biological processes crucial developing innovative therapeutic strategies targeting signaling. This review focuses on research progress cancers, providing in-depth insights into potential mechanisms regulation occurrence progression cancer. Additionally, summarizes pharmaceutical clinical trials therapy, aiming offer new human malignancies.

Язык: Английский

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The Fibrillin‐1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

Cancer Communications, Год журнала: 2022, Номер 42(3), С. 245 - 265

Опубликована: Март 1, 2022

Abstract Background Chemotherapy resistance is a primary reason of ovarian cancer therapy failure; hence it important to investigate the underlying mechanisms chemotherapy and develop novel potential therapeutic targets. Methods RNA sequencing cisplatin‐resistant ‐sensitive (chemoresistant chemosensitive, respectively) organoids was performed, followed by detection expression level fibrillin‐1 (FBN1) in clinical specimens cancer. Subsequently, glucose metabolism, angiogenesis, chemosensitivity were analyzed structural glycoprotein FBN1‐knockout cell lines. To gain insights into specific functions action FBN1 cancer, immunoprecipitation, silver nitrate staining, mass spectrometry, immunofluorescence, Western blotting, Fӧrster resonance energy transfer‐fluorescence lifetime imaging analyses vivo assays using vertebrate model systems nude mice zebrafish. Results significantly enhanced tissues, indicating that might be key factor chemoresistance We also discovered sustained stress induced angiogenesis vitro vivo, which promoted cisplatin‐resistance Knockout combined with treatment antiangiogenic drug apatinib improved cisplatin‐sensitivity cells. Mechanistically, mediated phosphorylation vascular endothelial growth receptor 2 (VEGFR2) at Tyr1054 residue, activated its downstream focal adhesion kinase (FAK)/protein B (PKB or AKT) pathway, signal transducer activator transcription (STAT2) tyrosine residue 690 (Tyr690), nuclear translocation STAT2, ultimately altered genes associated STAT2‐mediated glycolysis. Conclusions The FBN1/VEGFR2/STAT2 signaling axis may induce cells participating process glycolysis angiogenesis. present study suggested FBN1‐targeted and/or combination inhibition for treating

Язык: Английский

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4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 159, С. 114301 - 114301

Опубликована: Янв. 25, 2023

Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas investigation, particularly in cancers. present study aimed explore the role colorectal cancer progression. genetic alterations colon were evaluated using database. MTT assays, colony formation, flow cytometry used examine effect elesclomol-Cu 4-Octyl itaconate (4-OI) on oxaliplatin-resistant viability. anti-tumor elesclomol with 4-OI was verified vivo assay. results showed that FDX1, SDHB, DLAT, DLST genes more highly expressed normal tissues than those primary tumor tissues. Patients high expressions these had better prognosis. Using assay formation analysis, pulse treatment significant inhibition viability HCT116, LoVo, HCT116-R cells. In addition, revealed significantly promoted apoptosis. Tetrathiomolybdate, copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy-D-glucose, glucose metabolism inhibitor, sensitized Furthermore, galactose further Interestingly, enhanced which irrelevant ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis through GAPDH, one key enzymes glycolysis, sensitizing Meanwhile, FDX1 knockdown weakened ability promote experiments, effects. These indicated rapidly halted growth cells line. Importantly, aerobic targeting GAPDH

Язык: Английский

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