The Warburg effect: a score for many instruments in the concert of cancer and cancer niche cells

Pharmacological Reports, Journal Year: 2023, Volume and Issue: 75(4), P. 876 - 890

Published: June 19, 2023

Abstract Although Warburg's discovery of intensive glucose uptake by tumors, followed lactate fermentation in oxygen presence was made a century ago, it is still an area intense research and development new hypotheses that, layer layer, unravel the complexities neoplastic transformation. This seemingly simple metabolic reprogramming cancer cells reveals intriguing, multi-faceted nature that may link various phenomena including cell signaling, proliferation, ROS generation, energy supply, macromolecules synthesis/biosynthetic precursor immunosuppression, or cooperation cancerous with cancer-associated fibroblasts (CAFs), known as reversed Warburg effect. According to current perception causes consequences effect, PI3K/Akt/mTOR are main signaling pathways concert transcription factors HIF-1, p53, c-Myc, modulate activity/expression key regulatory enzymes, PKM2, PDK1 tune most optimal setting for cell. turn secures adequate levels biosynthetic precursors, NADPH, NAD + , rapid ATP production meet increased demands intensively proliferating tumor cells. The end-product “aerobic glycolysis”, lactate, oncometabolite, provide fuel neighboring cells, facilitate metastasis immunosuppression together enabling progression. importance possible applicability presented issue best illustrated numerous trials agents targeting constituting promising strategy future anti-cancer regimens. In this review, we present aspects multifactorial phenomenon, depicting mechanisms benefits behind also pointing selected field anticancer therapy.

Language: Английский

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Metabolic regulation of the immune system in health and diseases: mechanisms and interventions

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 9, 2024

Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes functions of immune cells. The regulation system is important in pathogenesis progression numerous diseases, such as cancers, autoimmune diseases diseases. concept immunometabolism was introduced over a decade ago to elucidate intricate interplay between metabolism immunity. definition has expanded from chronic low-grade inflammation reprogramming cells various With being proposed developed, can be gradually summarized becomes more clearer. In context many cancer, disease, occurs inducing proinflammatory or anti-inflammatory effects. phenotypic functional changes caused by further affect development Based on experimental results, targeting cellular promising therapy. this review, we focus introduce their pathways reprogramming, summarize how these effects We thoroughly explore targets treatments based existing studies. challenges translating results into clinical applications field are also summarized. believe that better understanding health will improve management most

Language: Английский

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Crosstalk between metabolism and cell death in tumorigenesis

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 4, 2024

Abstract It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs resist adverse environmental events, modify metabolic pathways produce both extra energies substances required for growth. Realizing characters special will be helpful eliminating them during therapy. Cell death a hot topic long-term study targeting cell one most effective ways repress Many studies have successfully demonstrated metabolism inextricably linked Here we summarize recently identified specifically impact on different types deaths discuss roles in tumorigenesis.

Language: Английский

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Carbonic anhydrase IX: An atypical target for innovative therapies in cancer

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(4), P. 189120 - 189120

Published: May 25, 2024

Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX a tumor-associated isoform induced by hypoxia and involved the adaptation of tumor cells to acidosis. Indeed, tumor-driving pathways can induce expression, this turn has been associated cancer invasion metastatic features as well induction stem-like features, drug resistance recurrence. After its functional structural characterization targeting approaches have developed inhibit activity neoplastic tissues, date field seen an incredible acceleration terms therapeutic options biological readouts. Small molecules inhibitors, hybrid/dual drugs, antibodies adoptive (CAR-T based) cell therapy at preclinical level, whereas sulfonamide inhibitor antibody entered Phase Ib/II clinical trials for treatment imaging different solid tumors. Here recent advances on biology pharmacology cancer, will be discussed.

Language: Английский

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AMPK–a key factor in crosstalk between tumor cell energy metabolism and immune microenvironment?

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: May 18, 2024

Abstract Immunotherapy has now garnered significant attention as an essential component in cancer therapy during this new era. However, due to immune tolerance, immunosuppressive environment, tumor heterogeneity, escape, and other factors, the efficacy of immunotherapy been limited with its application very small population size. Energy metabolism not only affects progression but also plays a crucial role escape. Tumor cells are more metabolically active need energy nutrients maintain their growth, which causes surrounding lack glucose, oxygen, nutrients, result decreased cell activity increased cells. On hand, utilize multiple metabolic pathways, for instance, cellular respiration, oxidative phosphorylation pathways normal function. Studies have shown that there is difference expenditure resting activated states. Notably, competitive uptake glucose main cause impaired T Conversely, glutamine competition often activation most transformation CD4 + into inflammatory subtypes. Excessive metabolite lactate impairs function NK Furthermore, PGE2 inhibits response by inhibiting Th1 differentiation, B function, activation. Additionally, tumor-suppressive M1 macrophages cancer-promoting M2 influenced metabolism. Therefore, vital factor involved reconstruction microenvironment. Noteworthy does program affect antigen presentation recognition cells, own functions, ultimately leading changes Metabolic intervention can improve tumors, increase immunogenicity thereby expanding who benefit from immunotherapy. Consequently, identifying crosstalk molecules link microenvironment would be promising anti-tumor strategy. AMPK (AMP-activated protein kinase) ubiquitous serine/threonine kinase eukaryotes, serving central regulator pathways. The sequential associated signaling cascades profoundly impacts dynamic alterations bioenergetics. By modulating responses, exerts influence on development, while playing pivotal regulating AMPK-mediated facilitates recruitment (TIME), impeding tumorigenesis, progression, metastasis. AMPK, between homeostasis, bioenergetics, immunity, will impact treatment management oncology patients. That being summarized, objective review pinpoint provide guidance development strategies.

Language: Английский

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Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 16, 2024

Abstract Histone post-translational modifications (HPTMs), as one of the core mechanisms epigenetic regulation, are garnering increasing attention due to their close association with onset and progression diseases potential targeted therapeutic agents. Advances in high-throughput molecular tools abundance bioinformatics data have led discovery novel HPTMs which similarly affect gene expression, metabolism, chromatin structure. Furthermore, a growing body research has demonstrated that histone also play crucial roles development various diseases, including cancers, cardiovascular infectious psychiatric disorders, reproductive system diseases. This review defines nine modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, 2-hydroxybutyrylation. It comprehensively introduces modification processes these HPTMs, transcription, replication, DNA repair recombination, structure, well involvement promoting occurrence clinical applications targets biomarkers. Moreover, this provides detailed overview HPTM inhibitors targeting emerging strategies treatment multiple while offering insights into future prospects challenges. Additionally, we briefly introduce techniques field research.

Language: Английский

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GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: April 4, 2024

Abstract Background Lactate has emerged as a critical regulator within the tumor microenvironment, including glioma. However, precise mechanisms underlying how lactate influences communication between cells and tumor-associated macrophages (TAMs), most abundant immune in glioma, remain poorly understood. This study aims to elucidate impact of tumor-derived on TAMs investigate regulatory pathways governing TAM-mediated tumor-promotion Methods Bioinformatic analysis was conducted using datasets from TCGA CGGA. Single-cell RNA-seq were analyzed by UCSC Cell Browser Single Portal. proliferation mobility evaluated through CCK8, colony formation, wound healing, transwell assays. Western blot immunofluorescence staining applied assess protein expression cell distribution. RT-PCR ELISA employed identify potential secretory factors. Mechanistic explored western blotting, ELISA, shRNA knockdown, specific inhibitors activators. The effects pathway blockades further assessed subcutaneous intracranial xenograft models vivo. Results Elevated expressions LDHA MCT1 observed glioma exhibited positive correlation with M2-type TAM infiltration. derived induced towards M2-subtype polarization, subsequently promoting proliferation, migration, invasion, mesenchymal transition. GPR65, highly expressed TAMs, sensed lactate-stimulation TME, fueling malignant progression secretion HMGB1. GPR65 triggered HMGB1 release response stimulation via cAMP/PKA/CREB signaling pathway. Disrupting this feedback loop GPR65-knockdown or inhibition mitigated Conclusion These findings unveil intricate interplay mediated HMGB1, driving selectively fostered Blocking presents promising therapeutic strategy for GBM.

Language: Английский

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Genetics of glycosylation in mammalian development and disease

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: May 9, 2024

Language: Английский

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Context-dependent role of SIRT3 in cancer

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(2), P. 173 - 190

Published: Jan. 19, 2024

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Lactate and lactylation in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 11, 2025

Abstract Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation fate regulation in physiological pathological settings, particularly intricate conditions such as cancer. Specifically, been demonstrated to be pivotal molding tumor microenvironment (TME) through its effects different cell populations. Within cells, impacts signaling pathways, augments shuttle process, boosts resistance oxidative stress, contributes lactylation. In various populations, interplay between immune cells governs processes differentiation, response, surveillance, treatment effectiveness. Furthermore, communication stromal/endothelial supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, drug resistance. Focusing production transport, specifically dehydrogenase (LDH) monocarboxylate transporters (MCT), shown promise Inhibitors targeting LDH MCT act both suppressors enhancers immunotherapy, leading a synergistic therapeutic effect when combined with immunotherapy. The review underscores importance progression provides valuable perspectives potential approaches that target vulnerability metabolism, highlighting Heel Achilles for cancer treatment.

Language: Английский

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