In
prostate cancer, oxidative stress and the subsequent Nrf2 activation promote the survival of
cancer cells and acquired chemoresistance. Nrf2 links
prostate cancer to endoplasmic reticulum stress, an event that triggers the unfolded protein response, aiming to restore cellular homeostasis as well as an adaptive survival mechanism.
Glucose-regulated
protein of 78 kD /
immunoglobulin heavy chain binding protein (
GRP78/BiP) is a key
molecular chaperone in the endoplasmic reticulum that, when expressed at the cell surface, acts as a receptor for several signaling pathways enhancing antiapoptotic and proliferative signals. We showed
GRP78/BiP translocation to PC3 cell surface in the presence of
tunicamycin, an ER stress inductor, and demonstrated the existence of a
GRP78/BiP-dependent non-canonical Nrf2 activation, responsible for increased resistance to ER-stress induced apoptosis. We found that, even in the absence of ROS production,
tunicamycin causes Nrf2 activation, and activates Akt signaling, events bulnted by anti-
GRP78/BiP antibody treatment. The presence of
GRP78/BiP at the cell surface might be exploited for the immunotherapeutic strategy of
prostate cancer since its blockage by anti-
GRP78/BiP
antibodies might promote
cancer death by suppressing some of the several molecular protective mechanisms found in aggressive
cancer cells.