Folate pathways mediating the effects of ethanol in tumorigenesis
Introduction
Folate and alcohol are dietary factors affecting the risk of cancer development in humans [[1], [2], [3], [4]]. This conclusion is primarily based on numerous epidemiological studies; precise molecular mechanisms underlying the link between alcohol consumption or folate metabolism and cancer initiation and progression remain largely unknown. The assessment of the combined effect of these two dietary components is obviously more intricate and is a challenging task at molecular, cellular, organism and population levels [5]. The problem is exacerbated by the fact that effects of both folate intake and alcohol consumption are cancer type-specific and can be also modified by other dietary components as well as the personal genetic and epigenetic landscape [[6], [7], [8], [9]]. Thus, though alcohol consumption has been investigated as a potential risk factor for numerous cancers, epidemiological studies have linked it more strongly to the increased risk of breast cancer, cancers of digestive tract and upper respiratory tract [10,11]. Even with regard to these cancer types, the relationship between alcohol and cancer is not simple. For example, the study of 2812 breast cancer cases from the French E3N-EPIC cohort concluded that there were no association between high alcohol consumption and increased risk of breast cancer among premenopausal women but found a positive linear correlation among post-menopausal women [12]. Of note, this study also indicated that low folate intake increased alcohol-associated breast cancer risk [12]. Some reports also imply that moderate alcohol consumption could be associated with decreased cancer risk especially in the context of specific diets like Mediterranean diet [[13], [14], [15]]. Nevertheless, the prevalent view in the literature is that alcohol consumption is associated with the increased risk of several cancers while folate supplementation can reduce this risk [11,16,17]. Accordingly, this review considers potential mechanisms underlying such effects (schematically depicted in Fig. 1).
Section snippets
Role of folate in tumorigenesis and malignancy progression
Several mechanisms for ethanol's effect on carcinogenesis have been proposed, including the induction of oxidative stress, acetaldehyde-associated mutagenesis, perturbation of estrogen metabolism, and via folate metabolism (reviewed in [5,18,19]). Folate is an important dietary component because humans cannot synthesize it [20]. In the cell, folate functions as a coenzyme in numerous reactions of one-carbon transfer, which are required for the de novo purine and TMP biosynthesis, NADPH
Folate transport and ethanol-induced folate deficiency
Folate was one of the factors intensively investigated with regard to the effect of alcohol consumption (reviewed in [[41], [42], [43]]). Studies from the early 1960s demonstrated that folate deficiency is common among alcoholics and that the positive hematopoietic response to the folate intake in these patients could be completely suppressed by excessive alcohol amounts [44,45]. Recent studies in animals have confirmed these findings. Thus, rats subjected to chronic ethanol ingestion had
Folate degradation
Reduced folates are unstable in vitro and rapidly undergo oxidative degradation but they are protected from degradation in the cell through binding to numerous folate enzymes [66]. Despite of such protection, in vivo folate catabolism is an active process [[67], [68], [69], [70]]. The degradation of folate can be non-enzymatic but is also catalyzed by ferritin [71]. As alcohol consumption induces folate deficiency, the question has been asked of whether ethanol contributes to enhanced folate
Effect of ethanol on folate metabolizing enzymes
Reactions constituting folate metabolism are carried out by about two dozen of specific enzymes [21]. The functions of many of these enzymes have been linked to tumorigenesis and malignancy progression [20,[84], [85], [86]]. Several of these enzymes are well-known targets of ethanol [42]. Thus, ethanol has been shown to produce inhibitory effect on the activities of MTHFR and MTR in an animal model [87]. This mechanism can contribute to carcinogenesis by affecting the liver S-adenosylmethionine
Molecular mechanisms underlying effects of ethanol on folate homeostasis
The interaction between alcohol consumption and dietary folate intake is relevant not only to cancer but also to liver diseases and disorders of embryonic development. Indeed, studies in micropigs have shown that folate deficiency enhances perturbations in hepatic methionine metabolism, decreases S-adenosylmethionine and glutathione, and increases DNA damage and lipid oxidation while promoting alcoholic liver injury [103,104]. As well, both alcohol consumption and dietary folate deficiency have
microRNA link between alcohol consumption and dietary folate
Alcohol consumption was also investigated with regard to the role of microRNAs (miRNAs) in the teratogenic, liver damaging and carcinogenic effects of ethanol (reviewed in [[139], [140], [141], [142]]). miRNAs, a diverse class of highly conserved small non-coding RNAs that regulate gene expression, play important role in malignant tumor initiation and in metastasis [[143], [144], [145]]. A recent analysis of RNA-Seq paired-end dataset derived from alcohol-exposed neural fold-stage chick crania
Folate, ethanol and oxidative stress
Folate can alleviate oxidative stress [172,173] while ethanol is a known inducer of such stress [[174], [175], [176]]. Ethanol metabolism generates reactive oxygen species and depletes the antioxidant molecule glutathione (GSH) which leads to oxidative stress and lipid and protein damage and then to growth retardation and neurotoxicity [177,178]. The relationship between alcohol consumption and folate intake is a two-way street: ethanol can decrease folate-dependent antioxidative capacity while
Summary
Mountains of literature link alcohol consumption and folate intake to the risk of cancer development. While alcohol consumption has positive correlation with the risk of several types of cancer, numerous studies support the idea that increased dietary folate has inverse correlation with tumorigenesis. However, precise molecular mechanisms underlying the effects of ethanol and folate in this respect are diverse and not completely understood. Several of these mechanisms involve the effect of
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors thank Dr. David Horita for carefully reading the manuscript and thoughtful comments. S.A.K. is supported by the National Institutes of Health grant R01 DK117854.
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