Evolutionary View on Lactate-Dependent Mechanisms of Maintaining Cancer Cell Stemness and Reprimitivization

The role of lactic acid (lactate) in cell metabolism has been significantly revised in recent decades. Initially, lactic acid was attributed to the role of a toxic end-product of metabolism, with its accumulation in the cell and extracellular space leading to acidosis, muscle pain, and other adverse effects. However, it has now become obvious that lactate is not only a universal fuel molecule and the main substrate for gluconeogenesis but also one of the most ancient metabolites, with a signaling function that has a wide range of regulatory activity. The Warburg effect, described 100 years ago (the intensification of glycolysis associated with high lactate production), which is characteristic of many malignant tumors, confirms the key role of lactate not only in physiological conditions but also in pathologies. The study of lactate’s role in the malignant transformation becomes more relevant in the light of the “atavistic theory of carcinogenesis,” which suggests that tumor cells return to a more primitive hereditary phenotype during microevolution. In this review, we attempt to summarize the accumulated knowledge about the functions of lactate in cell metabolism and its role in the process of carcinogenesis and to consider the possible evolutionary significance of the Warburg effect.

Shegay Petr V. 1 , Zabolotneva Anastasia A. 2 , Shatova Olga P.2, 3 , Shestopalov Aleksandr V.2, 4 , Kaprin Andrei D. 1, 3
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  • 1 Federal State Budget Institution National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation
  • 2 Department of Biochemistry and Molecular Biology, Faculty of Medicine, Pirogov Russian National Research Medical University
  • 3 Faculty of Medicine, RUDN University
  • 4 Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Health of the Russian Federation
Ключевые слова
lactate; lactic acid; glycolysis; carcinogenesis; malignant tumors; evolutionary oncology
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Journal of Medicinal Chemistry. American Chemical Society. Том 65. 2022. С. 8227-8244