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Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.

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Fig. 1: Modulators of aerobic glycolysis and potential anti-cancer therapeutics.
Fig. 2: The mechanism of GAPDH in the regulation of glycolysis and cancer cell growth.
Fig. 3: The mechanism for the conversion of 3-phosphoglycerate to 2-phosphoglycerate through PGAM1.
Fig. 4: The roles of ENO1 in cancer.
Fig. 5: The stability of HIF-1 under normoxic and hypoxia conditions.
Fig. 6: Post-translational modifications of key enzymes in glycolysis.
Fig. 7: Strategies for the regulation of enzymes in the glycolysis.

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Acknowledgements

The work was supported by the National Key R&D Program of China (2019YFA0802400), the National Natural Science Foundation of China (82000237 and 32171437), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (22KJB310017), Gusu Key Health Talent Program of Suzhou (GSWS2022122), the Priority Academic Program Development (PAPD) of the Jiangsu Higher Education Institutions of China, and Gusu Talent Program.

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  1. Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China

    Xuan Ni & Jing-jing Ma

  2. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China

    Cheng-piao Lu & Guo-qiang Xu

  3. Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Guo-qiang Xu

  4. MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, China

    Guo-qiang Xu

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Ni, X., Lu, Cp., Xu, Gq. et al. Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01264-1

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