Alcohol and Prostate Cancer: Time to Draw Conclusions

Abstract

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.

Keywords: alcohol consumption; ethanol metabolism; prostate cancer; prostate cancer-associated mortality.

Figure 1

Alcohol metabolism in prostate cells. The main enzymatic breakdown of EtOH is mediated by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). In the cytoplasm (1), ADH metabolizes alcohol to acetaldehyde (ACH), a highly toxic substance and a known carcinogen. In addition, ACH induces endoplasmic reticulum (ER) stress and Golgi disorganization. Then, in the mitochondria (2), acetaldehyde is converted to less active byproduct acetate, breaking down into water and carbon dioxide for elimination. However, chronic alcohol consumption activates alternative pathways of EtOH metabolism. EtOH can be converted to ACH via microsomal cytochrome P450 2E1 (CYP2E1) enzyme (3) or by catalase in peroxisomes (4). The latter reactions are associated with the production of ROS. Excessive production of acetate and accumulation of NADH in mitochondria results in the conversion of ACH into acetate catalyzed by cytoplasmic or microsomal xanthine oxidase (XO). Additionally, acetate can be converted into acetyl CoA (catalyzed by acetyl-CoA synthetase (ACS)) followed by the activation of purine degradation. Oxidations of hypoxanthine to xanthine and xanthine to uric acid are also catalyzed by XO, which contributes to free-radical production. Numbers 1, 2, 3, and 4 indicate localization of enzymatic reactions in the cytoplasm, mitochondria, ER, and peroxisome, accordingly.

Figure 2

Geographical distribution of the case-control and cohort studies of alcohol association with risk of PCa. Note that epidemiological observations founding strong association between alcohol and PCa risk (A) represent a larger number of countries (23) than those denying such a link ((B), 13 countries).

Figure 3

Distribution of epidemiological observations published before and after the implementation of PSA testing in 1995. We found 12 manuscripts published between 1980 and 1995 that deny any link or report a weak association between alcohol consumption habit and risk of PCa. Within these years, only five publications reported the positive connection. In the observations published from 1995 to the present, the ratio of publications showing no link:positive link was shifted to 18:65. There is a significant difference between the publication years of articles with positive correlation and those with no correlation (Mann–Whitney test, * p < 0.0001; median ± SD, the median for no correlation is 1998, median for positive correlation is 2014).

Figure 4

The impact of alcohol-induced Golgi disorganization on prostate carcinogenesis. (A) In normal prostate cells or low aggressive PCa cells, HDAC6 is distributed in both the nucleus and the cytoplasm. Typically, the phosphorylation of HDAC6 is moderate because the enzyme that phosphorylates HDAC6, GSK3β, is sequestered primarily within the Golgi. The acetylated HSP90 has a limited binding capacity to AR. EtOH treatment results in Golgi fragmentation and translocation of GSK3β to the cytoplasm, which results in increased phosphorylation of HDAC6. HDAC6-P deacetylates HSP90, which, in turn, accelerates conformational maturation of AR, its binding to DHT, and translocation to the nucleus. (B) In normal prostate and low-aggressive PCa cells, ATF6α is cleaved sequentially in the Golgi by S1P and S2P proteases. The dimeric form of trans-golgin GCC185 is the retention partner for both S1P and S2P. Cleaved ATF6 enters the nucleus and binds to ER stress-response elements, stimulating the expression of UPR genes. EtOH and its metabolites fragment Golgi membranes, which is associated with the monomerization of GCC185 and the subsequent shift of S1P and S2P to the ER. This simplifies and accelerates ATF6 cleavage, resulting in more prominent UPR signaling to maintain tumor cell growth and proliferation.

Figure 5

Alcohol interference in the development and progression of PCa. (A) Alcohol is a critical player and driver of prostate carcinogenesis. The carcinogenic effects of EtOH and its metabolites are magnified by multiple cofactors, such as obesity, smoking, excessive high-fat and red meat diet, low-level consumption of fish, caffeine, and linoleic acid, low physical activity, SNP of alcohol-related genes, and family history of PCa. Additional factors may include income and marital status: unmarried patients with an unstable financial situation are at higher risk of PCa. (B) In patients diagnosed with PCa, alcohol’s contribution to prostate tumor progression does not require cofactors. EtOH metabolites are sufficient to drive tumor growth and raise the metastatic potential of cancer cells.