V-ATPase:结构、功能及其在肿瘤细胞中的作用

V-ATPase:structure,function and roles in tumor cells

真核细胞膜及管泡细胞器膜上广泛分布一种与H+主动转运有关的蛋白——V-ATPase。V-AT-Pase的结构由跨膜的V0和细胞质内的V1两个亚单位组成,前者为H+提供通道,后者能分解ATP,为逆浓度梯度转运H+提供能量。V0和V1只有在聚合时,V-ATPase全酶才有功能。肿瘤细胞中V-ATPase的过度表达或过度活跃,遏制了由酵解增强乳酸聚集导致的细胞内酸化趋势,使细胞避免了凋亡的命运。而H+排至细胞外,改变蛋白水解酶的活性,使细胞外基质分解增强,细胞更有侵袭力。肿瘤细胞的V-ATPase可望成为抑制细胞增生、扩散的有效靶点。

The vacuolar (H+)-ATPase is a membrane-related protein in eukaryotic cells which can pump H+ outside ofthe cells or into the lumens of some vacuolar organelles to maintain the cytoplasmic pH in a relatively stable neutrallevel which is essential for the cells survival and to acidify some intracellular apartments which is necessary for thefunctions of endosomes, lysosomes and Golgi apparatus. The holoenzyme is composed of the membrane sector V0and the cytoplasmic sector V1. Only when V1 attaches to V0, can H+ go through the transmembrane hydrophilic pathof V0 to the opposite side of the membrane, using the energy from the ATP hydrolyzed by V1. The main regulation ofthe activity of the holoenzyme relies on the reversible attachment or disattachment of V1 and V0. The defectivenessof any subunit, the effects of some non-V-ATPase proteins or the small molecular inhibitors, the changes of themicroenvironment around the cells or the changes of the metabolism within the cells will interrupt the activity of theholoenzyme which will then lead to the re-distribution of H+ and change the fate of the cells in the end. Tumor cellsare inclined to be intracellular acidified resulted from changed metabolism which may be activated by loss of theoxygen supply. Nonetheless, the over-activated V-ATPase helps the cells to maintain cytoplasmic pH normal andtherefore to escape the fate of apoptosis. The extracellullar over-leaked H+ will re-build the crosstalk between the cellsand the ECM (extracellular matrix) which will in turn interfere many signal pathways inside the cells. Following that,many behaviors of the tumor cells like invasion, angiogenesis or multi-drug-resistant were modified to be optimizedfor the survival of the cells. Thus, the over-activated V-ATPase may be an initial and enhancing factor of theaggressive growth of tumors and therefore is qualified to be a candidate target for the therapy of tumor.