Abstract 1330: Golgi disorganization and ER stress: the mechanism underlying alcohol-mediated prostate cancer progression

Abstract

The link between prostate cancer (PCa) risk and alcohol consumption has long been debated. In our recent analysis of the epidemiologic evidence for this link, we found that, since the onset of the PSA testing era, a preponderance of studies indicates ethanol (EtOH) consumption is strongly associated with PCa risk. Despite epidemiologic support for this relationship, little is known about the underlying mechanisms. Our group introduced the concept of “onco-Golgi,” where the Golgi becomes fragmented alongside activating transcription factor 6 (ATF6)-mediated Endoplasmic Reticulum (ER) stress. This results in increased plasma membrane (PM) expression of abnormally glycosylated αv Integrins by Golgi glycosyltransferase, N-acetylglucosaminyltransferase-V (MGAT5). Importantly, these MGAT5-modified integrins bind to pentameric Galectin-3, resulting in clustering and increased retention on the PM. This, in turn, modulates tumor cell behavior, including adhesion to extracellular matrix and migration, leading to acceleration of prostate tumor dissemination to lymph nodes and distant organs, including bones. We have also found the EtOH treatment causes further Golgi disorganization. PCa tissues from heavy alcoholic patients demonstrate higher MGAT5 expression and elevated Integrin αv levels on the PM. We propose that EtOH promotes PCa lethality by increasing Integrin αv-mediated PCa progression. Altered glycosylation of Integrin αv in the onco-Golgi is expected to be exacerbated by alcohol’s disorganizing effect on Golgi. We have found a positive correlation between the number of Golgi fragments and the intensity of Integrin αv on the PM in both docetaxel-resistant PC-3 and DU145 cells after EtOH treatment. Importantly, we revealed that Golgi disorganization in advanced PCa cells is an autophagy-driven process. We found that autophagy inhibitor, Hydroxychloroquine (HCQ), restores compact Golgi in both PC-3 and DU145 cells, as well as in mice orthotopic PC-3-derived tumors. The effect of HCQ was strengthened by depletion of ATF6, suggesting the synergetic effect of autophagy inhibition and alleviation of ER stress. Significantly, HCQ treatment attenuates the EtOH-induced Golgi fragmentation and restores the level of PM Integrin αv to that of control cells. We expect that our established protocol to restore Golgi morphology and inhibit ER stress by HCQ treatment and ATF6 depletion, respectively, will attenuate the impact of EtOH on PCa cells. Overall, these data shed light on alcohol-promoting effects on prostate tumor growth and metastasis and provide a potentially effective therapeutic strategy. Citation Format: Amanda Macke, Artem Pachikov, Taylor Divita, Armen Petrosyan. Golgi disorganization and ER stress: the mechanism underlying alcohol-mediated prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1330.