Kobliakov V A
Blokhin Russian Cancer Research Center, Russian Ministry of Health, Moscow, 115478, Russia.
Biochemistry (Mosc). 2017 Apr;82(4):401-412. doi: 10.1134/S0006297917040010.
One of the differences between normal and cancer cells is lower pH of the extracellular space in tumors. Low pH in the extracellular space activates proteases and stimulates tumor invasion and metastasis. Tumor cells display higher level of the HIF1α transcription factor that promotes cell switch from mitochondrial respiration to glycolysis. The terminal product of glycolysis is lactate. Lactate formation from pyruvate is catalyzed by the specific HIF1α-dependent isoform of lactate dehydrogenase A. Because lactate accumulation is deleterious for the cell, it is actively exported by monocarboxylate transporters. Lactate is cotransported with proton, which acidifies the extracellular space. Another protein that contributes to proton concentration increase in the extracellular space is tumor-specific HIF1α-dependent carbonic anhydrase IX, which generates a proton in the reaction between carbon dioxide and water. The activity of Na+/H+ exchanger (another protein pump) is stimulated by stress factors (e.g. osmotic shock) and proliferation stimuli. This review describes the mechanisms of proton pump activation and reviews results of studies on effects of various proton pump inhibitors on tumor functioning and growth in cell culture and in vivo. The prospects of combined application of proton pump inhibitors and cytostatics in cancer therapy are discussed.
正常细胞与癌细胞之间的差异之一在于肿瘤细胞外空间的pH值较低。细胞外空间的低pH值会激活蛋白酶，并刺激肿瘤侵袭和转移。肿瘤细胞中促细胞从线粒体呼吸转变为糖酵解的HIF1α转录因子水平较高。糖酵解的终产物是乳酸。丙酮酸形成乳酸是由乳酸脱氢酶A的特定HIF1α依赖性同工型催化的。由于乳酸积累对细胞有害，它会通过单羧酸转运体被主动输出。乳酸与质子协同转运，从而使细胞外空间酸化。另一种导致细胞外空间质子浓度增加的蛋白质是肿瘤特异性HIF1α依赖性碳酸酐酶IX，它在二氧化碳与水的反应中产生一个质子。Na+/H+交换体（另一种蛋白质泵）的活性受应激因素（如渗透休克）和增殖刺激的激发。本综述描述了质子泵激活的机制，并综述了各种质子泵抑制剂对细胞培养和体内肿瘤功能及生长影响的研究结果。还讨论了质子泵抑制剂与细胞抑制剂联合应用于癌症治疗的前景。
