Skip to main content
placeholder image

A possible mechanism for the enhanced activation of plasminogen on malignant breast cancer cells

Journal Article


Abstract


  • Glu-plasminogen (pig) exists in solution in a lysine (lys)-dependent closed conformation and binds to its cell-surface receptors via its lys binding sites. In vitro analysis of the binding of pig to a-enolase using BIAcore technology, fluorescence spectroscopy and ELISA'2 suggested that this interaction is complex and involves lys-dependent competition reactions that induce conformational changes to the zymogen, thereby increasing its activation rate. We hypothesise that metastatic breast cancer cells which have a high cell surface pig and urokinase binding capacity, such as MDA-MB-231 ', bind pig by a similar mechanism resulting in rapid activation and high levels of cell-associated plasmin activity. Lys-dependent competition inhibition of pig binding to MDA-MB-231 cells by tranexamic acid (TA) resulted in an ICW of 0.3 HIM, which is comparable to the concentration of TA required to induce a half-maximal conformational change in pig. In contrast, the competitive, lys-dependent dissociation of cell-bound pig by TA had an apparent IC50 100-fold greater than pig. These data confirm that pig binds to cell-surface receptors with high affinity in an open conformation that accelerates pig activation. Several distinct pig binding proteins have been detected in the plasma membranes of MDA-MB-231 cells and the non-metastatic, very low pig binding and activation cell lines MCF-7 and T-47D'. However, at the cell surface these cell lines express the same known pig receptors to a similar degree, despite their differential capacities for pig binding and activation. It is possible that an initial binding and activation event made possible by the presence of receptor bound urokinase on the MDA-MB-231 but not MCF-7 or T-47D cells3 generates enough bound plasmin to rapidly generate new pig binding sites (ie C-terminal lysines). This would result in the observed significantly higher pig binding capacity of the MDA-MB-231 cell line compared to the other cell lines which would lead, in turn, to the enhanced plasmin activity of the MDA-MB-23) cells.

Publication Date


  • 2000

Citation


  • Ranson, M., & Ronicos, N. M. (2000). A possible mechanism for the enhanced activation of plasminogen on malignant breast cancer cells. Fibrinolysis and Proteolysis, 14(SUPPL. 1), 11.

Scopus Eid


  • 2-s2.0-33846990990

Web Of Science Accession Number


Start Page


  • 11

Volume


  • 14

Issue


  • SUPPL. 1

Abstract


  • Glu-plasminogen (pig) exists in solution in a lysine (lys)-dependent closed conformation and binds to its cell-surface receptors via its lys binding sites. In vitro analysis of the binding of pig to a-enolase using BIAcore technology, fluorescence spectroscopy and ELISA'2 suggested that this interaction is complex and involves lys-dependent competition reactions that induce conformational changes to the zymogen, thereby increasing its activation rate. We hypothesise that metastatic breast cancer cells which have a high cell surface pig and urokinase binding capacity, such as MDA-MB-231 ', bind pig by a similar mechanism resulting in rapid activation and high levels of cell-associated plasmin activity. Lys-dependent competition inhibition of pig binding to MDA-MB-231 cells by tranexamic acid (TA) resulted in an ICW of 0.3 HIM, which is comparable to the concentration of TA required to induce a half-maximal conformational change in pig. In contrast, the competitive, lys-dependent dissociation of cell-bound pig by TA had an apparent IC50 100-fold greater than pig. These data confirm that pig binds to cell-surface receptors with high affinity in an open conformation that accelerates pig activation. Several distinct pig binding proteins have been detected in the plasma membranes of MDA-MB-231 cells and the non-metastatic, very low pig binding and activation cell lines MCF-7 and T-47D'. However, at the cell surface these cell lines express the same known pig receptors to a similar degree, despite their differential capacities for pig binding and activation. It is possible that an initial binding and activation event made possible by the presence of receptor bound urokinase on the MDA-MB-231 but not MCF-7 or T-47D cells3 generates enough bound plasmin to rapidly generate new pig binding sites (ie C-terminal lysines). This would result in the observed significantly higher pig binding capacity of the MDA-MB-231 cell line compared to the other cell lines which would lead, in turn, to the enhanced plasmin activity of the MDA-MB-23) cells.

Publication Date


  • 2000

Citation


  • Ranson, M., & Ronicos, N. M. (2000). A possible mechanism for the enhanced activation of plasminogen on malignant breast cancer cells. Fibrinolysis and Proteolysis, 14(SUPPL. 1), 11.

Scopus Eid


  • 2-s2.0-33846990990

Web Of Science Accession Number


Start Page


  • 11

Volume


  • 14

Issue


  • SUPPL. 1