Fibrinogen - a possible extracellular target for inositol phosphates.
Grint T., Riley AM., Mills SJ., Potter BVL., Safrany ST.
A potential extracellular target for inositol phosphates and analogues with anticancer properties is identified. Proteins from detergent-solubilised HeLa cell lysates bound to a novel affinity column ofmyo-inositol 1,3,4,5,6-pentakisphosphate (InsP5) coupled to Affigel-10. One high-affinity ligand was fibrinogen Bβ. Inositol phosphates and analogues were able to elute purified fibrinogen from this matrix. InsP5and the inositol phosphate mimic biphenyl 2,3',4,5',6-pentakisphosphate (BiPhP5) bind fibrinogenin vitro, and block the effects of fibrinogen in A549 cell-based assays of proliferation and migration. They are also able to prevent the fibrinogen-mediated activation of phosphatidylinositol 3-kinase. These effects of fibrinogen appear to be mediated through the intercellular adhesion molecule-1 (ICAM-1), as cells not expressing ICAM-1 fail to respond. In contrast,myo-inositol hexakisphosphate and the epimericscyllo-inositol 1,2,3,4,5-pentakisphosphate were without effect. These findings are consistent with earlier reports that higher inositol phosphates have anticancer properties. This new mechanism of action and target for these extracellular inositol phosphates to have their effects allows a re-evaluation of earlier data.