Fig. 8

The working model of the self-activating mechanism of ER stress-mediated survival in PCa cells. (A) ATF6α is a 90 kDa type II transmembrane glycoprotein, which is transferred to the Golgi in normal prostate and low-aggressive PCa cells, where it undergoes cleavage by two proteases, S1P and S2P. These proteases are retained in the trans-Golgi by the dimeric form of GCC185. S1P and S2P sequentially remove the luminal domain and the transmembrane anchor of ATF6, respectively, mobilizing a 50 kDa N-terminal cytoplasmic fragment p50, which, in turn, enters the nucleus and binds to ER stress-response elements, stimulating the expression of UPR mediators. Thus, the number of ATF6 molecules transported to the Golgi correlates with the level of UPR. (B) In advanced PCa cells, Golgi’s disorganization is associated with the monomerization of GCC185, evoking translocation of both S1P and S2P to the ER and subsequent excessive cleavage of ATF6 molecules. Subsequently, high UPR signaling provides sufficient expression of chaperones that are required for AR-mediated tumor cell growth and proliferation