posted on 2023-10-31, 22:03authored byRitu Bhardwaj, Prashant Mishra
Erythropoietin-producing
hepatocellular (Eph) receptors and their
ligands, ephrins, are the largest subfamily of receptor tyrosine kinases
(RTKs) that have emerged as a new class of cancer biomarkers due to
their aberrant expression in cancer progression. The activation of
Eph receptors either due to their hyperexpression or via high affinity
binding with their respective ephrin ligands initiates a cascade of
signals that impacts cancer development and progression. In prostate
cancer, the overexpression of the EphA6 receptor has been correlated
with increased metastatic potential. Azurin, a small redox protein,
is known to prevent tumor progression by binding to cell surface Eph
receptors, inhibiting its autophosphorylation in the kinase domain
and thereby disrupting Eph–ephrin signaling. Hence, a self-assembled,
theranostic nanosystem of recombinant fusion protein his6EGFP-azu (80–128) was designed by conjugating enhanced green
fluorescent protein (EGFP) with the C-terminal region of azurin. This
design was inspired by the in silico binding study,
where the analogue of ephrinA, his6EGFP-azu (80–128)
showed higher binding affinity for the EphA6 receptor than the ephrinA
ligands. The his6EGFP-azu (80–128) nanosystem which
assembled as nanoparticles was tested for its ability to simultaneously
detect and kill the prostate cancer cells, LNCaP. This was achieved
by specifically targeting EphA6 receptors overexpressed on the cancer
cell surface via C-terminal peptide, azu (80–128). Herein,
we report antiproliferative, apoptotic, antimigratory, and anti-invasive
effects of this nanosystem on LNCaP cells, while having no similar
effects on EphA6 negative human normal lung cells, WI-38.