Membrane lipid rafts are highly ordered microdomains and essential components of plasma membranes. In this work, we demonstrate that
azurin uptake by
cancer cells is, in part, mediated by
caveolin-1 and GM-1,
lipid rafts' markers. This recognition is mediated by a surface exposed hydrophobic core displayed by
azurin since the substitution of a
phenylalanine residue in position 114 facing the hydrophobic cavity by
alanine impacts such interactions, debilitating the uptake of
azurin by
cancer cells. Treating of
cancer cells with
azurin leads to a sequence of events: alters the
lipid raft exposure at plasma membranes, causes a decrease in the plasma membrane order as examined by
Laurdan two-photon imaging and leads to a decrease in the levels of
caveolin-1. Caveolae, a subset of
lipid rafts characterized by the presence of
caveolin-1, are gaining increasing recognition as mediators in
tumor progression and resistance to standard
therapies. We show that
azurin inhibits growth of
cancer cells expressing
caveolin-1, and this inhibition is only partially observed with mutant
azurin. Finally, the simultaneous administration of
azurin with anticancer therapeutic drugs (
paclitaxel and
doxorubicin) results in an enhancement in their activity, contrary to the mutated
protein.