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. In vitro studies suggest that EtOH-induced downregulation of MGAT3 correlates with activation of MGAT5-mediated glycosylation and overexpression of both matriptase and integrins. In sum, we provide a novel insight into the alcohol-mediated tumor promotion.
{"title":"THE IMPACT OF ALCOHOL ON PRO-METASTATIC N-GLYCOSYLATION IN PROSTATE CANCER.","authors":"A V Kubyshkin, I I Fomochkina, A M Petrosyan","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>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. <i>In vitro</i> studies suggest that EtOH-induced downregulation of MGAT3 correlates with activation of MGAT5-mediated glycosylation and overexpression of both matriptase and integrins. In sum, we provide a novel insight into the alcohol-mediated tumor promotion.</p>","PeriodicalId":92687,"journal":{"name":"Krimskii zhurnal eksperimental'noi i klinicheskoi meditsiny = Kryms'kyi zhurnal eksperymental'noi ta klinichnoi medytsyny = Crimean journal of experimental and clinical medicine","volume":"8 4","pages":"11-20"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534161/pdf/nihms-1020234.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37275340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Krimskii zhurnal eksperimental'noi i klinicheskoi meditsiny = Kryms'kyi zhurnal eksperymental'noi ta klinichnoi medytsyny = Crimean journal of experimental and clinical medicine
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