Azurin is a member of a family of
metalloproteins called cupredoxins. Although previously thought to be involved in electron transfer,
azurin has recently been shown to preferentially enter
cancer cells than normal cells and induce apoptosis in such cells.
Azurin also demonstrates structural similarity to a
ligand known as ephrinB2, which binds its cognate
receptor tyrosine kinase EphB2 to initiate cell signaling. Eph/
ephrin signaling is known to be involved in
cancer progression. We now demonstrate that
azurin binds to the EphB2-Fc receptor with high affinity. We have localized a C-terminal domain of
azurin (Azu 96-113) that exhibits structural similarity to ephrinB2 at the G-H loop region known to be involved in receptor binding. A synthetic
peptide (Azu 96-113) as well as a GST fusion derivative GST-Azu 88-113 interferes with the growth of various human
cancer cells. In a
prostate cancer cell line DU145 lacking functional EphB2,
azurin or its GST-fusion derivatives had little cytotoxic effect. However, in DU145 cells expressing functional EphB2,
azurin and GST-Azu 88-113 demonstrated significant cytotoxicity, whereas ephrinB2 promoted cell growth.
Azurin inhibited the ephrinB2-mediated autophosphorlyation of the EphB2
tyrosine residue, thus interfering in upstream cell signaling and contributing to
cancer cell growth inhibition.