Kobliakov V A
Tsitologiia. 2016;58(7):499-506.
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.
本综述探讨了缺氧和糖酵解在癌症发展中的作用。实验结果表明，糖酵解在肿瘤细胞中的功能不仅限于提供能量。糖酵解刺激转录因子HIF1a的活性。HIF1a与蛋白ARNT形成复合物，刺激众多基因的表达。这些基因包括编码糖酵解蛋白、端粒酶、P-糖蛋白、属于bcl2家族的抗凋亡蛋白、丙酮酸脱氢酶抑制剂——丙酮酸脱氢酶激酶、去分化基因等的基因。通过抑制丙酮酸脱氢酶来抑制线粒体呼吸链，会刺激丙酮酸在细胞内积累。乳酸脱氢酶将丙酮酸转化为乳酸。肿瘤细胞中乳酸的积累会激活单羧酸转运体。结果，乳酸和质子被释放到细胞外空间。肿瘤组织的pH值下降。低pH值促进各种降解细胞间基质的蛋白酶的活性。在低pH值水平的肿瘤区域观察到侵袭增强。肿瘤组织中正常pH值水平的恢复会抑制侵袭和转移。因此，可以得出结论，缺氧是一种刺激并维持肿瘤进程的细胞生理状态。有氧糖酵解（瓦伯格效应）即使在细胞充分氧合的情况下也会刺激肿瘤生长。文中给出了关于瓦伯格效应机制的现代观点。还讨论了使用糖酵解不同阶段的抑制剂作为单一抗癌药物或与传统抗癌化合物联合使用的可能性。
