How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation DOI Open Access

Zoé Daverio,

Aneta Balcerczyk, Gilles J. P. Rautureau

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(5), P. 1417 - 1417

Published: Feb. 23, 2023

Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered side effect metabolism, lactic acidosis is now known to play major role in physiology, aggressiveness treatment efficiency. Growing evidence shows that it promotes cell resistance glucose deprivation, common feature tumours. Here we review current understanding how extracellular acting as combination enzymatic inhibitors, signal, nutrient, switch metabolism an oxidative metabolic phenotype, which allows withstand makes promising anticancer target. We also discuss about acidosis’ could be integrated whole-tumour what perspectives opens up for future research.

Language: Английский

Genetically predicted 486 blood metabolites in relation to risk of colorectal cancer: A Mendelian randomization study DOI Creative Commons
Zhangjun Yun, Ziwei Guo, Xiao Li

et al.

Cancer Medicine, Journal Year: 2023, Volume and Issue: 12(12), P. 13784 - 13799

Published: May 3, 2023

Metabolic disorders are a hallmark feature of cancer. However, the evidence for causality circulating metabolites to promote or prevent colorectal cancer (CRC) is still lacking. We performed two-sample Mendelian randomization (MR) analysis assess from genetically proxied 486 blood CRC.Genome-wide association study (GWAS) data exposures were extracted 7824 Europeans GWAS on metabolite levels. CRC catalog database GCST012879 used preliminary analysis. The random inverse variance weighted (IVW) primary while MR-Egger and median as complementary analyses. Cochran Q test, intercept MR-PRESSO, Radial MR, leave-one-out sensitivity For significant associations, additional independent GCST012880 replication meta-analysis. final identification metabolites, Steiger linkage disequilibrium score regression, colocalization further evaluation. Multivariable MR was direct effect CRC.The results this indicated associations between six pyruvate (odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.32-0.77, p = 0.002), 1,6-anhydroglucose (OR: 1.33, CI: 1.11-1.59, nonadecanoate (19:0) 0.40, C I:0.4-0.68, 0.0008), 1-linoleoylglycerophosphoethanolamine 0.47, 0.30-0.75, 0.001), 2-hydroxystearate 0.39, 0.23-0.67, 0.0007), gamma-glutamylthreonine 2.14, 1.02-4.50, 0.040) CRC. MVMR revealed that predicted pyruvate, can directly influence independently other metabolites.The current work provides support new perspective exploration biological mechanisms by combining genomics metabolomics. These findings contribute screening, prevention treatment

Language: Английский

Citations

63
Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics? DOI
Mamta Singh, Julieta Afonso, Dolly Sharma

et al.

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 90, P. 1 - 14

Published: Jan. 24, 2023

Language: Английский

Citations

61
Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation DOI Creative Commons
Ting Sun, Bin Liu, Yanyan Li

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Sept. 29, 2023

Abstract Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of inducing the formation microenvironment remains be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed orthotopic xenografts nude mice using flow cytometry assay immunohistochemical staining after oxamate, a dehydrogenase A (LDHA) inhibitor, control T or cells injection alone combination. RT-qPCR, western blot, cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation ELISA performed measure effect on regulation CD39, CD73 CCR8 cultured glioma stem cells, CD4 + macrophages. Results Oxamate promoted immune activation tumor-infiltrating through altering phenotypes molecules increasing regulatory (Treg) infiltration glioblastoma mouse model. Lactate accumulation within upregulated expressions both lactate-treated cells-co-cultured macrophages, intracellular directly elevated activities these gene promotors histone H3K18 lactylation. Conclusions Utilizing generation inhibitor not only reprogramed glucose metabolism cancer but also alleviated immunosuppression reduced CAR-Treg which may potential strategy enhance function therapy.

Language: Английский

Citations

43
A Multichannel Metabolic Pathway Interference Strategy for Complete Energy Depletion‐Mediated Cancer Therapy DOI
He Ding,

Jianye Wei,

Linyang Fang

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: 34(19)

Published: Jan. 18, 2024

Abstract Hydrogen sulfide (H 2 S) is being progressively integrated as an emerging inhibitor of the electron transport chain in energy interference‐based tumor therapy. However, metabolic reprogramming cancer cells causes both oxidative phosphorylation (OXPHOS) and glycolysis to occur simultaneously, which contributes ineffective therapeutic effect blocking a single pathway. To achieve complete suppression production, inorganic H S donor ZnS@ZIF‐8@CaP nanoparticle (ZSZC NP) carrying Ca Zn constructed for achieving simultaneous interference OXPHOS glycolysis. The core–shell ZSZC nanoparticles can break down microenvironment. This leads sustained release calcium overload disrupt normal functioning mitochondria by inhibiting expression cytochrome c causing damage mitochondrial membrane potential. Meanwhile, presence 2+ hinders typical process impeding lactate dehydrogenase glyceraldehyde‐3‐phosphate dehydrogenase. synchronous hampers supply cells. Additionally, expedite necrosis vivo inducing cellular acidification calcification. Therefore, this energy‐blocking strategy will completely deplete reserves provide new insights exploring bioenergetic inhibition treatment approach.

Language: Английский

Citations

30
Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives DOI Creative Commons
Chenliang Zhang, Tingting Huang, Liping Li

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Aug. 16, 2024

Cuproptosis is a newly identified form of cell death induced by excessive copper (Cu) accumulation within cells. Mechanistically, cuproptosis results from Cu-induced aggregation dihydrolipoamide S-acetyltransferase, correlated with the mitochondrial tricarboxylic acid cycle and loss iron–sulfur cluster proteins, ultimately resulting in proteotoxic stress triggering death. Recently, has garnered significant interest tumor research due to its potential as crucial therapeutic strategy against cancer. In this review, we summarized cellular molecular mechanisms relationship other types Additionally, reviewed current drugs or strategies available induce cells, including Cu ionophores, small compounds, nanomedicine. Furthermore, targeted metabolism specific regulatory genes cancer therapy enhance sensitivity cuproptosis. Finally, discussed feasibility targeting overcome chemotherapy immunotherapy resistance suggested future directions. This study that could open new avenues for developing therapy.

Language: Английский

Citations

18
GLUT and HK: Two primary and essential key players in tumor glycolysis DOI
Dhiraj Yadav,

Anubha Yadav,

Sujata Bhattacharya

et al.

Seminars in Cancer Biology, Journal Year: 2024, Volume and Issue: 100, P. 17 - 27

Published: March 15, 2024

Language: Английский

Citations

17
Lactate and lactylation in cancer DOI Creative Commons
Jie Chen, Ziyue Huang,

Ya Chen

et al.

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

Citations

9
Targeting glycolysis: exploring a new frontier in glioblastoma therapy DOI Creative Commons
Lu Yang, Sijia Li, Lei Yu

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 14, 2025

Glioblastoma(GBM) is a highly malignant primary central nervous system tumor that poses significant threat to patient survival due its treatment resistance and rapid recurrence.Current options, including maximal safe surgical resection, radiotherapy, temozolomide (TMZ) chemotherapy, have limited efficacy.In recent years, the role of glycolytic metabolic reprogramming in GBM has garnered increasing attention. This review delves into pivotal GBM, with particular focus on multifaceted roles lactate, key product, within microenvironment (TME). Lactate been implicated promoting cell proliferation, invasion, immune evasion. Additionally, this systematically analyzes potential therapeutic strategies targeting molecules pathway, such as Glucose Transporters (GLUTs), Monocarboxylate Transporters(MCTs), Hexokinase 2 (HK2), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), Pyruvate Kinase Isozyme Type M2 (PKM2), Dehydrogenase A (LDHA). These studies provide novel perspective for treatment. Despite progress made existing research, challenges remain, drug penetration across blood-brain barrier, side effects, resistance. Future research will aim address these by improving delivery, minimizing exploring combination therapies immunotherapy develop more precise effective personalized GBM.

Language: Английский

Citations

2
Lactate Drives Senescence-Resistant Lineages in Hepatocellular Carcinoma via Histone H2B Lactylation of NDRG1 DOI
Lu Li, Jinyun Dong,

Chunwei Xu

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217567 - 217567

Published: Feb. 1, 2025

Language: Английский

Citations

2
Functions and mechanisms of lactylation in carcinogenesis and immunosuppression DOI Creative Commons

Jing Su,

Zhuangzhuang Zheng,

Chenbin Bian

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 14, 2023

As critical executors regulating many cellular operations, proteins determine whether living activities can be performed in an orderly and efficient manner. Precursor are inert must modified posttranslationally to enable a wide range of protein types functions. Protein posttranslational modifications (PTMs) well recognized as being directly associated with carcinogenesis immune modulation have emerged important targets for cancer detection treatment. Lactylation (Kla), novel PTM metabolism found cells, interacts both histone nonhistone proteins. Unlike other epigenetic changes, Kla has been linked poor tumor prognosis all current studies. Histone affect gene expression tumors immunological thereby promoting malignancy immunosuppression. Nonhistone also regulate progression treatment resistance through Kla. In this review, we aimed summarize the role onset cancers, metabolic reprogramming, immunosuppression, intestinal flora regulation identify new molecular therapy provide direction combined targeted immunotherapy.

Language: Английский

Citations

26