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 well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. 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.

Alcohol and Prostate Cancer: Time to Draw Conclusions

“…The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with AR signaling, different disease stages, and alcohol consumption. Significantly, the depletion of ATF6 retarded the growth of xenograft prostate tumors and blocked the production of pro-metastatic metabolites [220]. Another important observation from our study is that in PCa patients consuming alcohol, cribriform patterns in the tumor area (a clinically significant prognostic indicator for advanced PCa) were larger than in non-alcoholic patients.…”

“…glass of wine-1 or more times per day; 3.4 oz. of strong liquor at least once per day) [220]. We found that alcohol-induced Golgi disorganization was associated with monomerization of trans-golgin, GCC185, the Golgi retention partner of S1P and S2P.…”

ROS and Endoplasmic Reticulum Stress in Pulmonary Disease

“…As a result, several ER stress response element genes such as GRP78, GRP94, CHOP can be activated, and promote the ER associated protein degradation gene XBP1 (X-box binding protein 1) transcription. The ATF6f can bind XBP1 and control the expression of some specific genes ( Zhang et al, 2019b ; Pachikov et al, 2021 ).…”

Role of ER Stress in Xenobiotic-Induced Liver Diseases and Hepatotoxicity

“…The mechanisms involved in regulating cell apoptosis under the conditions of irreversible ER stress are now partially understood, and multiple pathways are involved in ER-mediated cell apoptosis [ 8 ]. PERK and IRE1 are type-I transmembrane proteins, which could act on their downstream targets after phosphorylation, while type II transmembrane kinase ATF6 needs to be spliced by site 1 protease (S1P) and site 2 protease (S2P) in the Golgi apparatus before translocating into the nucleus to induce the transcription of its downstream target [ 10 ]. All three targets can promote apoptosis by activating the transcription of the growth arrest and DNA damage-inducible protein 34 (GADD34) and C/EBP homologous protein (CHOP), which are essential for cell apoptosis.…”