Lactate and Lactylation in Gastrointestinal Cancer: Current Progress and Perspectives (Review)

Overview

Journal Oncol Rep

Specialty Oncology

Date 2024 Nov 8

PMID 39513579

Authors

Yufen He

Yaxi Huang

Peng Peng

Qi Yan

Lidan Ran

Affiliations

Soon will be listed here.

Abstract

Gastrointestinal (GI) cancers, which have notable incidence and mortality, are impacted by metabolic reprogramming, especially the increased production and accumulation of lactate. Lactylation, a post‑translational modification driven by lactate, is a crucial regulator of gene expression and cellular function in GI cancer. The present review aimed to examine advancements in understanding lactate and lactylation in GI cancer. The mechanisms of lactate production, its influence on the tumor microenvironment and the clinical implications of lactate levels as potential biomarkers were explored. Furthermore, lactylation was investigated, including its biochemical foundation, primary targets and functional outcomes. The present review underscored potential therapeutic strategies targeting lactate metabolism and lactylation. Challenges and future directions emphasize the potential of lactate and lactylation as innovative therapeutic targets in GI cancer to improve clinical outcomes.

References

Tay C, Tanaka A, Sakaguchi S . Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell. 2023; 41(3):450-465. DOI: 10.1016/j.ccell.2023.02.014. View

Caslin H, Abebayehu D, Pinette J, Ryan J . Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function. Front Physiol. 2021; 12:688485. PMC: 8558259. DOI: 10.3389/fphys.2021.688485. View

Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N . The cancer metabolic reprogramming and immune response. Mol Cancer. 2021; 20(1):28. PMC: 7863491. DOI: 10.1186/s12943-021-01316-8. View

Wang F, Yi J, Chen Y, Bai X, Lu C, Feng S . PRSS2 regulates EMT and metastasis via MMP-9 in gastric cancer. Acta Histochem. 2023; 125(6):152071. DOI: 10.1016/j.acthis.2023.152071. View

Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X . Histone lactylation drives oncogenesis by facilitating mA reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 2021; 22(1):85. PMC: 7962360. DOI: 10.1186/s13059-021-02308-z. View

Xie N, Zhang L, Gao W, Huang C, Huber P, Zhou X . NAD metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct Target Ther. 2020; 5(1):227. PMC: 7539288. DOI: 10.1038/s41392-020-00311-7. View

Zhai X, Yang Y, Wan J, Zhu R, Wu Y . Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells. Oncol Rep. 2013; 30(6):2983-91. DOI: 10.3892/or.2013.2735. View

Wang J, Yang P, Yu T, Gao M, Liu D, Zhang J . Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages. Int J Biol Sci. 2022; 18(16):6210-6225. PMC: 9682528. DOI: 10.7150/ijbs.75434. View

Jiang J, Huang D, Jiang Y, Hou J, Tian M, Li J . Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer. Front Oncol. 2021; 11:647559. PMC: 8208031. DOI: 10.3389/fonc.2021.647559. View

10.

Dichtl S, Lindenthal L, Zeitler L, Behnke K, Schlosser D, Strobl B . Lactate and IL6 define separable paths of inflammatory metabolic adaptation. Sci Adv. 2021; 7(26). PMC: 8221612. DOI: 10.1126/sciadv.abg3505. View

11.

Lu W, Zhang L, Ji K, Ding L, Wu G . Regulatory mechanisms of GCN5 in osteogenic differentiation of MSCs in periodontitis. Clin Exp Dent Res. 2023; 9(3):464-471. PMC: 10280614. DOI: 10.1002/cre2.695. View

12.

Hadjihambi A, Konstantinou C, Klohs J, Monsorno K, Le Guennec A, Donnelly C . Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction. J Hepatol. 2022; 78(1):180-190. DOI: 10.1016/j.jhep.2022.08.008. View

13.

Wang T, Ye Z, Li Z, Jing D, Fan G, Liu M . Lactate-induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer. Cell Prolif. 2023; 56(10):e13478. PMC: 10542650. DOI: 10.1111/cpr.13478. View

14.

Li X, Yang Y, Zhang B, Lin X, Fu X, An Y . Lactate metabolism in human health and disease. Signal Transduct Target Ther. 2022; 7(1):305. PMC: 9434547. DOI: 10.1038/s41392-022-01151-3. View

15.

Lin Y, Yuksel Durmaz Y, Nor J, ElSayed M . Synergistic combination of small molecule inhibitor and RNA interference against antiapoptotic Bcl-2 protein in head and neck cancer cells. Mol Pharm. 2013; 10(7):2730-8. PMC: 4043997. DOI: 10.1021/mp4001662. View

16.

Wang P, Xie D, Xiao T, Cheng C, Wang D, Sun J . H3K18 lactylation promotes the progression of arsenite-related idiopathic pulmonary fibrosis via YTHDF1/m6A/NREP. J Hazard Mater. 2023; 461:132582. DOI: 10.1016/j.jhazmat.2023.132582. View

17.

She X, Wu Q, Rao Z, Song D, Huang C, Feng S . SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle. Adv Sci (Weinh). 2023; 10(28):e2301871. PMC: 10558670. DOI: 10.1002/advs.202301871. View

18.

Schwab M, Thunborg K, Azimzadeh O, von Toerne C, Werner C, Shevtsov M . Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response. Cancers (Basel). 2021; 13(15). PMC: 8345170. DOI: 10.3390/cancers13153762. View

19.

Qu J, Li P, Sun Z . Histone lactylation regulates cancer progression by reshaping the tumor microenvironment. Front Immunol. 2023; 14:1284344. PMC: 10641494. DOI: 10.3389/fimmu.2023.1284344. View

20.

Xie B, Lin J, Chen X, Zhou X, Zhang Y, Fan M . CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer. Mol Cancer. 2023; 22(1):151. PMC: 10486081. DOI: 10.1186/s12943-023-01856-1. View