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.