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.
Lipotoxic stress-induced β-cell death (lipotoxicity) is recognized as a key contributor to the development of type 2 diabetes mellitus (T2DM). The current study reports a critical role of sphingosine kinase 1 (SphK1) in β-cell survival under lipotoxic conditions. In an attempt to investigate the role of SphK1 in lipotoxicity in vivo, we fed Sphk1(-/-) and wild-type (WT) mice with a high-fat diet (HFD) or normal chow diet. Remarkably, while HFD-fed WT mice developed glucose intolerance and compensatory hyperinsulinemia, all HFD-fed Sphk1(-/-) mice manifested evident diabetes, accompanied by a nearly 3-fold reduction in insulin levels compared with the WT mice. Pancreatic β-cell mass was increased by 140% in HFD-fed WT mice but decreased to 50% in HFD-fed Sphk1(-/-) mice, in comparison with the chow diet control groups, respectively. Accordingly, by blocking the enzyme activity, expression of a dominant negative form of SphK1 markedly promoted palmitate-induced cell death in MIN6 and INS-1 β-cell lines. Moreover, primary islets isolated from Sphk1(-/-) mice exhibited higher susceptibility to lipotoxicity than WT controls. Of note, sphingosine 1-phosphate (S1P) profoundly abrogated lipotoxicity in β cells or the cells lacking SphK1 activity and Sphk1(-/-) islets, highlighting a pivotal role of S1P in β-cell survival under lipotoxic conditions. These findings could suggest a new therapeutic strategy for preventing β-cell death and thus the onset of T2DM.
Key Points
Blockmirs are designed against the miR-27 binding site in VE-cadherin and display restricted specificity. Blockmirs regulate VE-cadherin and endothelial cell junctions, inhibit edema, and promote angiogenesis associated with ischemia.
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