THE IMPACT OF ALCOHOL ON PRO-METASTATIC N-GLYCOSYLATION IN PROSTATE CANCER.

Chronic alcohol abuse and alcoholism are considered risk factors for prostate cancer (PCa) progression, but the mechanism is unknown. Previously, we found that: (1) fragmentation of the Golgi complex correlates with the progression of PCa; (2) ethanol (EtOH) induces Golgi disorganization, which, in turn, alters intra-Golgi localization of some Golgi proteins. Also, progression of the prostate tumor is associated with activation of N-acetylglucosaminyltransferase-V (MGAT5)-mediated N-glycosylation of pro-metastatic proteins, including matriptase and integrins, followed by their enhanced retention at the cell surface. Here, using high-resolution microscopy, we found that alcohol effect on Golgi in low passage androgen-responsive LNCaP cells mimic the fragmented Golgi phenotype of androgen-refractory high passage LNCaP and PC-3 cells. Next, we detected that transition to androgen unresponsiveness is accompanied by downregulation of N-acetylglucosaminyltransferase-III (MGAT3), the enzyme that competes with MGAT5 for anti-metastatic N-glycan branching. Moreover, in low passage LNCaP cells, alcohol-induced Golgi fragmentation induced translocation of MGAT3 from the Golgi to the cytoplasm, while intra-Golgi localization of MGAT5 appeared unaffected. Then, the relationship between Golgi morphology, MGAT3 intracellular position, and clinicopathologic features was assessed in human PCa patient specimens with and without a history of alcohol dependence. We revealed that within the same clinical stage, the level of Golgi disorganization and the cytoplasmic shift of MGAT3 was more prominent in patients consuming alcohol.