HYPOXIA AND GLYCOLYSIS AS FACTORS DETERMINING THE MALIGNANT PHENOTYPE

The review deals with the role of hypoxia and glycolysis in the development of cancer. Experimental results demonstrate that the function of glycolysis in tumour cells is not limited to providing energy. Glycolysis stimulates the activity of transcription factor HIF1a. HIF1a in complex with protein ARNT stimulates expression of numerous genes. There are genes encoding proteins of glycolysis, telomerase, P-glycoproteins, antiapoptotic proteins belonging to bcl2 family, inhibitor of pyruvate dehydrogenase—pyruvate dehydrogenase kynase, dedifferentiation genes and others. Inhibition of mitochondria respiratory chain by inhibiting of pyruvate dehydrogenase stimulates accumulation of pyruvate in the cell. Lactate dehydrogenase transforms pyruvate on lactate. Accumulation of lactate in tumour cells activates monocarboxylate transporter. As a result, lactate and proton are displayed in the intercellular space. There is a drop in the pH in tumour tissue. The low pH promotes the activity of various proteases that degrade intercellular matrix. The enhancement of invasion is observed in tumours area with low pH level. The restoration of normal pH level in tumour tissue inhibits invasion and metastasis. Thus, it is possible to conclude that hypoxia is a physiological state of cells that stimulates and mantaines tumour process. Aerobic glycolisis (Warburg effect) stimulates tumour growth even in the case of sufficient oxygenation of the cells. Modern views on the mechanism of the Warburg effect is given. The possibility of using inhibitors of different stages of glycolysis as mono anticancer agents or in combination with conventional anticancer compounds is discussed.