Secretion of phosphoglycerate kinase from tumour cells is controlled by oxygen-sensing hydroxylases.
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 tumour 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.
Daly
Elise B
EB
Centre for and Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, NSW 2031, Australia.
Wind
Troels
T
Jiang
Xing-Mai
XM
Sun
Lisa
L
Hogg
Philip J
PJ
D043168:Angiostatins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006900:Hydroxylation; D000860:Hypoxia / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000494:pharmacology; D010735:Phosphoglycerate Kinase / Q000096:biosynthesis / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; D006899:Mixed Function Oxygenases; D010735:Phosphoglycerate Kinase; D010100:Oxygen