Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase.
Disulphide bonds in secreted proteins are considered to be inert because of the oxidizing nature of the extracellular milieu. An exception to this rule is a reductase secreted by tumour cells that reduces disulphide bonds in the serine proteinase plasmin. Reduction of plasmin initiates proteolytic cleavage in the kringle 5 domain and release of the tumour blood vessel inhibitor angiostatin. New blood vessel formation or angiogenesis is critical for tumour expansion and metastasis. Here we show that the plasmin reductase isolated from conditioned medium of fibrosarcoma cells is the glycolytic enzyme phosphoglycerate kinase. Recombinant phosphoglycerate kinase had the same specific activity as the fibrosarcoma-derived protein. Plasma of mice bearing fibrosarcoma tumours contained several-fold more phosphoglycerate kinase, as compared with mice without tumours. Administration of phosphoglycerate kinase to tumour-bearing mice caused an increase in plasma levels of angiostatin, and a decrease in tumour vascularity and rate of tumour growth. Our findings indicate that phosphoglycerate kinase not only functions in glycolysis but is secreted by tumour cells and participates in the angiogenic process as a disulphide reductase.
Lay
A J
AJ
Centre for Thrombosis and Vascular Research, School of Pathology, University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, Australia.
Jiang
X M
XM
Kisker
O
O
Flynn
E
E
Underwood
A
A
Condron
R
R
Hogg
P J
PJ
D043168:Angiostatins; D000818:Animals; D017077:Culture Media, Conditioned; D004220:Disulfides / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D005354:Fibrosarcoma / Q000097:blood / Q000098:blood supply / Q000201:enzymology*; D006801:Humans; D018082:Kringles; D051379:Mice; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000097:blood; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism*; D010958:Plasminogen; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000201:enzymology; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D004220:Disulfides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D043168:Angiostatins; D010958:Plasminogen; D010735:Phosphoglycerate Kinase; D005341:Fibrinolysin