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 rul e is a reductase secreted by tumour cells that reduces disulphide bonds in the serine proteinase plasmin(1,2). Reduction of plasmin initiates proteoly tic cleavage in the kringle 5 domain and release of the tumour blood vessel inhibitor angiostatin(3). New blood vessel formation or angiogenesis is cr itical for tumour expansion and metastasis(4,5). Here we show that the plas min reductase isolated from conditioned medium of fibrosarcoma cells is the glycolytic enzyme phosphoglycerate kinase(6). Recombinant phosphoglycerate kinase had the same specific activity as the fibrosarcoma-derived protein. Plasma of mice bearing fibrosarcoma tumours contained several-fold more ph osphoglycerate kinase, as compared with mice without tumours. Administratio n of phosphoglycerate kinase to tumour-bearing mice caused an increase in p lasma levels of angiostatin, and a decrease in tumour vascularity and rate of tumour growth. Our findings indicate that phosphoglycerate kinase not on ly functions in glycolysis but is secreted by tumour cells and participates in the angiogenic process as a disulphide reductase.