Switching Roles─Exploring Concentration-Dependent Agonistic versus Antagonistic Behavior of Integrin Ligands

Identification of integrins as cancer targets has stimulated the development of specific inhibitory ligands. However, following cilengitide′s unexpected clinical failure by promoting angiogenesis at low concentrations, pure ligand antagonism was soon scrutinized. We evaluated αvβ3, αvβ6, or α5β1 ligands for concentration-dependent functional switches in respective integrin subtype-overexpressing cancer cells. Cilengitide (L2) or L1 provoked minor transient changes in (p)-FAK and (p)-p44/42^(erk-1/2) predominantly at low concentrations and antagonized cell migration at high concentrations, while agonistically accelerating it at low concentrations. L5 (α5β1) showed bell-shaped FAK activation at both concentrations, blocking cell migration at high concentrations only in α5β1+ OV-MZ-6 cells, not acting agonistically. L3 (αvβ6) did not alter signaling upon long exposure but transiently and early activated FAK in αvβ6+ HN cells at both concentrations, with neither antagonistic nor agonistic consequences on cell motility. These data underscore the need for in-depth evaluation of ligand actions to ensure their most promising medical use.