IBVF-CSIC, Avda. Americo Vespucio 49, 41092 Seville, Spain.
Curr Pharm Des. 2012;18(10):1383-94. doi: 10.2174/138161212799504821.
Cancer cells show a metabolic shift that makes them overproduce protons; this has the potential to disturb the cellular acid-base homeostasis. However, these cells show cytoplasmic alkalinisation, increased acid extrusion and endosome-dependent drug resistance. Vacuolar type ATPases (V-ATPases), together with other transporters, are responsible to a great extent for these symptoms. These multi-subunit proton pumps are involved in the control of cytosolic pH and the generation of proton gradients (positive inside) across endocellular membrane systems like Golgi, endosomes or lysosomes. In addition, in tumours, they have been shown to play an important role in the acidification of the intercellular medium. This importance makes them an attractive target to control tumour cell proliferation. In the present review we present the major characteristics of this kind of proton pumps and we provide some recent insights on their in vivo regulation. Also, we review some of the consequences that V-ATPase inhibition carries for the tumour cell, such as cell cycle arrest or cell death, and provide a brief summary of the studies related to cancer made recently with commercially available inhibitors. In the light of recent knowledge on the regulation of this proton pump, some new approaches to impair V-ATPase function are also suggested.
癌细胞表现出一种代谢转变，使它们过度产生质子；这有可能扰乱细胞的酸碱稳态。然而，这些细胞表现出细胞质碱化、酸外排增加和内体依赖性药物耐药性。液泡型 ATP 酶（V-ATPases）与其他转运体一起，在很大程度上负责这些症状。这些多亚基质子泵参与控制细胞质 pH 值和在内细胞膜系统（如高尔基体、内体或溶酶体）中产生质子梯度（正内）。此外，在肿瘤中，它们被证明在细胞外液的酸化中发挥重要作用。这种重要性使它们成为控制肿瘤细胞增殖的有吸引力的目标。在本综述中，我们介绍了这种质子泵的主要特征，并提供了一些关于其体内调节的最新见解。我们还回顾了 V-ATPase 抑制对肿瘤细胞的一些后果，如细胞周期停滞或细胞死亡，并简要总结了最近用商业上可获得的抑制剂进行的与癌症相关的研究。根据对这种质子泵调节的最新认识，还提出了一些削弱 V-ATPase 功能的新方法。
