Secretion of phosphoglycerate kinase from tumour cells is controlled by oxygen-sensing hydroxylases
Secretion of phosphoglycerate kinase from tumour cells is controlled by oxygen-sensing hydroxylases
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DOI：
10.1016/j.bbamcr.2003.11.004
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发表时间：
2004-04-01
影响因子：
5.1
通讯作者：
Hogg, PJ
中科院分区：
文献类型：
--
作者：
Daly, EB;Wind, T;Hogg, PJ
当实体肿瘤细胞的氧气供应受到限制时，它们利用糖酵解酶，包括磷酸甘油酸激酶（PGK）来制造ATP。PGK也由肿瘤细胞分泌，促进纤溶蛋白中二硫键的断裂，从而触发血管生成抑制剂血管抑制素的蛋白水解释放。虽然缺氧能增强肿瘤细胞产生PGK，但其分泌却受到抑制。抑制血管抑制素的分泌与减少血管抑制素的形成有关。相反，缺氧不抑制血管生成激活剂血管内皮细胞生长因子（VEGF）的分泌。正常缺氧可逆转PGK的分泌，并受氧感应蛋白羟化酶的控制，这类酶的抑制剂模拟了缺氧对PGK分泌的影响。PGK的直接羟基化并不是蛋白羟基化酶控制其分泌的机制。这些发现表明PGK的产生和分泌是分别受到调控的，表明氧和蛋白羟化酶不仅可以控制基因的表达，还可以控制蛋白的分泌。(C) 2003 Elsevier B.V.版权所有
Solid tumour cells employ glycolytic enzymes including phosphoglycerate kinase (PGK) to make ATP when their supply of oxygen is limiting. PGK is also secreted by tumour cells and facilitates cleavage of disulfide bonds in plasmin, which triggers proteolytic release of the angiogenesis inhibitor, angiostatin. Although PGK production by tumour cells was enhanced by hypoxia, its secretion was inhibited. Inhibition of secretion correlated with decrease in angiostatin formation by the turnour cells. In contrast, hypoxia did not inhibit the secretion of the angiogenesis activator, vascular endothelial cell growth factor (VEGF). PGK secretion was reversed by normoxia and was under control of the oxygen-sensing protein hydroxylases, as inhibitors of this class of enzymes mimicked the effect of hypoxia on PGK secretion. Direct hydroxylation of PGK was not the mechanism by which the protein hydroxylases controlled its secretion. These findings show that production and secretion of PGK are regulated separately and indicate that oxygen and the protein hydroxylases can control not only gene expression but also protein secretion. (C) 2003 Elsevier B.V. All rights reserved.