Fibrinogen - a possible extracellular target for inositol phosphates

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Inositol phosphates (IPs) and their analogues exhibit anticancer properties.
• The precise extracellular targets and mechanisms of action for these compounds remain incompletely understood.

Purpose of the Study:

• To identify novel extracellular targets of inositol phosphates with anticancer potential.
• To elucidate the mechanism by which certain inositol phosphates exert their effects on cancer cells.

Main Methods:

• Affinity chromatography using myo-inositol pentakisphosphate (InsP5) coupled to Affigel-10 to identify binding proteins from HeLa cell lysates.
• In vitro binding assays with purified fibrinogen and InsP5 or biphenyl pentakisphosphate (BiPhP5).
• Cell-based assays using A549 cells to assess the effects of InsP5 and BiPhP5 on proliferation, migration, and phosphatidylinositol 3-kinase activation, with and without intercellular adhesion molecule-1 (ICAM-1).

Main Results:

• Fibrinogen Bβ was identified as a high-affinity ligand for the InsP5 affinity column.
• InsP5 and BiPhP5 effectively eluted fibrinogen and demonstrated binding to it in vitro.
• InsP5 and BiPhP5 inhibited fibrinogen-mediated proliferation and migration in A549 cells, and prevented phosphatidylinositol 3-kinase activation.
• These inhibitory effects were dependent on the presence of ICAM-1.
• Myo-inositol hexakisphosphate and scyllo-inositol pentakisphosphate showed no significant effects.

Conclusions:

• Fibrinogen is a novel extracellular target for inositol phosphates with anticancer properties.
• Inositol phosphates, specifically InsP5 and BiPhP5, exert anticancer effects by binding to fibrinogen and interfering with fibrinogen-mediated signaling pathways, likely involving ICAM-1.
• This finding provides a new mechanism of action for extracellular inositol phosphates and allows for re-evaluation of previous data on their anticancer activities.