It has been a long-standing debate in the research and medical societies whether alcohol consumption is linked to the risk of prostate cancer (PCa). Many comprehensive studies from different geographical areas and nationalities have shown that moderate and heavy drinking is positively correlated with the development of PCa. Nevertheless, some observations could not confirm that such a correlation exists; some even suggest that wine consumption could prevent or slow prostate tumor growth. Here, we have rigorously analyzed the evidence both for and against the role of alcohol in PCa development. We found that many of the epidemiological studies did not consider other, potentially critical, factors, including diet (especially, low intake of fish, vegetables and linoleic acid, and excessive use of red meat), smoking, family history of PCa, low physical activity, history of high sexual activities especially with early age of first intercourse, and sexually transmitted infections. In addition, discrepancies between observations come from selectivity criteria for control groups, questionnaires about the type and dosage of alcohol, and misreported alcohol consumption. The lifetime history of alcohol consumption is critical given that a prostate tumor is typically slow-growing; however, many epidemiological observations that show no association monitored only current or relatively recent drinking status. Nevertheless, the overall conclusion is that high alcohol intake, especially binge drinking, is associated with increased risk for PCa, and this effect is not limited to any type of beverage. Alcohol consumption is also directly linked to PCa lethality as it may accelerate the growth of prostate tumors and significantly shorten the time for the progression to metastatic PCa. Thus, we recommend immediately quitting alcohol for patients diagnosed with PCa. We discuss the features of alcohol metabolism in the prostate tissue and the damaging effect of ethanol metabolites on intracellular organization and trafficking. In addition, we review the impact of alcohol consumption on prostate-specific antigen level and the risk for benign prostatic hyperplasia. Lastly, we highlight the known mechanisms of alcohol interference in prostate carcinogenesis and the possible side effects of alcohol during androgen deprivation therapy.

Prostate cancer progression to the lethal metastatic castration-resistant phenotype (mCRPC) is driven by αv integrins and is associated with Golgi disorganization and activation of the ATF6 branch of unfolded protein response (UPR). Overexpression of integrins requires N-acetylglucosaminyltransferase-V (MGAT5)-mediated glycosylation and subsequent cluster formation with Galectin-3 (Gal-3). However, the mechanism underlying this altered glycosylation is missing. For the first time, using HALO analysis of IHC, we found a strong association of integrin αv and Gal-3 at the plasma membrane (PM) in primary prostate cancer and mCRPC samples. We discovered that MGAT5 activation is caused by Golgi fragmentation and mislocalization of its competitor, N-acetylglucosaminyltransferase-III, MGAT3, from Golgi to the endoplasmic reticulum (ER). This was validated in an ethanol-induced model of ER stress, where alcohol treatment in androgen-refractory PC-3 and DU145 cells or alcohol consumption in patient with prostate cancer samples aggravates Golgi scattering, activates MGAT5, and enhances integrin expression at PM. This explains known link between alcohol consumption and prostate cancer mortality. ATF6 depletion significantly blocks UPR and reduces the number of Golgi fragments in both PC-3 and DU145 cells. Inhibition of autophagy by hydroxychloroquine (HCQ) restores compact Golgi, rescues MGAT3 intra-Golgi localization, blocks glycan modification via MGAT5, and abrogates delivery of Gal-3 to the cell surface. Importantly, the loss of Gal-3 leads to reduced integrins at PM and their accelerated internalization. ATF6 depletion and HCQ treatment synergistically decrease integrin αv and Gal-3 expression and temper orthotopic tumor growth and metastasis. Implications: Combined ablation of ATF6 and autophagy can serve as new mCRPC therapeutic.

Study of the novel RNA virus, Nora virus, which is a persistent, picorna-like virus that replicates in the gut of Drosophila melanogaster offers insight into human innate immunity and other picorna-like viruses. Nora virus infection leads to a locomotor abnormality and upregulation of two candidate target proteins, Vago and Virus-induced RNA 1 (Vir-1). These proteins are uncharacterized in response to Nora virus. We hypothesize that Nora virus is circulating in the hemolymph of Nora virus-infected D. melanogaster, allowing for migration beyond the primary site of replication in the gut. Analysis by qRT-PCR demonstrated biphasic viral load and corresponding vago and vir-1 transcription levels, suggesting transcription of vago and vir-1 occurs in response to viral infection. However, Vir-1 is also present in virus-free D. melanogaster suggesting basal expression or alternative functions. Presence of Nora virus RNA and the Viral Protein 4b (VP4b), in hemolymph of infected D. melanogaster supports the hypothesized circulation of Nora virus in the hemolymph. The study suggests that impaired locomotor function may be due to transport of Nora virus from the gut to the brain via the hemolymph.

Previous work from our laboratories has identified multiple defects in endocytosis, protein trafficking, and secretion, along with altered Golgi function after alcohol administration. Manifestation of alcohol‐associated liver disease (ALD) is associated with an aberrant function of several hepatic proteins, including asialoglycoprotein receptor (ASGP‐R), their atypical distribution at the plasma membrane (PM), and secretion of their abnormally glycosylated forms into the bloodstream, but trafficking mechanism is unknown. Here we report that a small GTPase, Rab3D, known to be involved in exocytosis, secretion, and vesicle trafficking, shows ethanol (EtOH)–impaired function, which plays an important role in Golgi disorganization. We used multiple approaches and cellular/animal models of ALD, along with Rab3D knockout (KO) mice and human tissue from patients with ALD. We found that Rab3D resides primarily in trans‐ and cis‐faces of Golgi; however, EtOH treatment results in Rab3D redistribution from trans‐Golgi to cis‐medial‐Golgi. Cells lacking Rab3D demonstrate enlargement of Golgi, especially its distal compartments. We identified that Rab3D is required for coat protein I (COPI) vesiculation in Golgi, and conversely, COPI is critical for intra‐Golgi distribution of Rab3D. Rab3D/COPI association was altered not only in the liver of patients with ALD but also in the donors consuming alcohol without steatosis. In Rab3D KO mice, hepatocytes experience endoplasmic reticulum (ER) stress, and EtOH administration activates apoptosis. Notably, in these cells, ASGP‐R, despite incomplete glycosylation, can still reach cell surface through ER‐PM junctions. This mimics the effects seen with EtOH‐induced liver injury. Conclusion : We revealed that down‐regulation of Rab3D contributes significantly to EtOH‐induced Golgi disorganization, and abnormally glycosylated ASGP‐R is excreted through ER‐PM connections, bypassing canonical (ER→Golgi→PM) anterograde transportation. This suggests that ER‐PM sites may be a therapeutic target for ALD.

Supplementary Table 3. The detailed information about orthotopic surgery, tumor sizes, and metastases.

Supplementary Table 4. The Chi-squared and Fisher's Exact tests of metastases in the group of mice with orthotopic tumor.