The non-canonical mechanism of ER stress-mediated progression of prostate cancer

Abstract

Background The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation. Methods Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP and 22RV1 cells, as wells as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds from different. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy. Results Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites. Conclusions We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.

The functional implication of ATF6α in castration‐resistant prostate cancer cells

“…Immunohistochemical analyses of PCa specimens confirmed the elevated expression and nuclear signal of ATF6α in tumors with higher Gleason scores. These data correlate ATF6α activity with PCa progression, and mirror its tumorigenic role in PCa cells that were also previously described in other PCa model systems 40,41 . In line with this, ATF6α ablation either genetically or chemically resulted in reduced viability and impaired survival in CRPC cells.…”

“…These data correlate ATF6α activity with PCa progression, and mirror its tumorigenic role in PCa cells that were also previously described in other PCa model systems. 40,41 In line with this, ATF6α ablation either genetically or chemically resulted in reduced viability and impaired survival in CRPC cells. These cell-based evidence potentiate a prosurvival role of ATF6α in CRPC cells and warrants preclinical evaluation of ATF6α inhibition in the future.…”