Polyamines, folic acid supplementation and cancerogenesis
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Gordana Bjelakovic
,
Dusica Pavlovic
Abstract
Clinical practice and experimental studies have shown the necessity of sufficient quantities of folic acid intake for normal embryogenesis and fetal development in the prevention of neural tube defects (NTDs) and neurological malformations. So, women of childbearing age must be sure to have an adequate folate intake periconceptionally, prior to and during pregnancy. Folic acid fortification of all enriched cereal grain product flour has been implemented in many countries. Thus, hundreds of thousands of people have been exposed to an increased intake of folic acid. Folate plays an essential role in the biosynthesis of methionine. Methionine is the principal aminopropyl donor required for polyamine biosynthesis, which is up-regulated in actively growing cells, including cancer cells. Folates are important in RNA and DNA synthesis, DNA stability and integrity. Clinical and epidemiological evidence links folate deficiency to DNA damage and cancer. On the other hand, long-term folate oversupplementation leads to adverse toxic effects, resulting in the appearance of malignancy. Considering the relationship of polyamines and rapidly proliferating tissues (especially cancers), there is a need for better investigation of the relationship between the ingestion of high amounts of folic acid in food supplementation and polyamine metabolism, related to malignant processes in the human body.
Introduction
Polyamine biochemistry and functions
The polyamines (PAs) diamine putrescine [H2N(CH2)4NH2], triamine spermidine (Spd) [H2N(CH2)3NH(CH2)4NH2] and spermine (Sp) [H2N(CH2)3NH(CH2)4NH(CH2)3NH2] (tetramine), are ubiquitous small basic molecules that play multiple essential roles in mammalian cell physiology. Despite the extensive research of their functions in physiology, they are not yet well understood [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11].
PAs have been implicated in diverse biological processes that are important for maintaining cell viability, including replication, transcription, translation, posttranslational modification, membrane stability and interactions with ion channels. They regulate cellular proliferation, transformation, differentiation, or cell growth and apoptosis, and especially tumorigenesis [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. In cells, PAs, as polycations, interact electrostatically with negatively charged moieties, such as DNA, RNA, phospholipids, mucopolysaccharides or various glycosaminoglycans (GAGs) and proteins. Binding to DNA, PAs play a significant role in stabilizing DNA, especially chromatin structure, during the cell cycle [23], [24], [25], [26], [27]. The affinity for binding to both DNA and RNA is: Sp>spermidine>putrescine. PAs stabilize the double helix of DNA, probably by forming a bridge across the narrow groove, involving electrostatic bonding with the phosphate group [27], [28], [29], [30], [31]. They occur in the free form as cations, but are often conjugated to various macromolecules [32]. Nuclear aggregates of PAs (NAPs) are formed by the formation of ionic bonds between PA ammonium and DNA phosphate groups. These aggregates of PAs with DNA influence, more efficaciously than single PAs, both the conformation and the protection of the DNA [28], [29], [30], [31], [32]. The interaction between NAPs and genomic DNA provides evidence for the decisive role of “natural” NAPs in the regulation of the important aspects of DNA physiology, such as conformation, protection and packaging, thus suggesting a new vision of the functions that PAs accomplish in the cell nucleus [30]. Spd is not concentrated in the nucleus [1], [25], [32], [33], [34], [35], [36].
The interactions of PAs with the components of membranes, such as phospholipids or negatively charged residues of membrane-bound proteins, could affect some properties of biological membranes [14], [15], [16], [17]. Also, the binding of PAs to RNA increases the efficiency of protein synthesis, as a substantial proportion of intracellular PAs is attached to the ribosomes. PAs are involved in the correct assembly of the ribosomal subunits during the process of protein synthesis. However, the common chemical or physical processes that can only operate in the presence of PAs have not yet been presented. Therefore, a better understanding of the role of PAs might reveal its key feature in cellular and molecular biology [12], [37], [38], [39].
Intracellular PA levels are regulated in a very fast, sensitive and precise manner. Cells have developed complex regulatory machinery for the maintenance and regulation of their intracellular homeostasis by their biosynthesis, catabolism and transport, namely the uptake and excretion mechanisms. The enzymes in PA metabolism are controlled at the level of transcription, translation and protein degradation. The complexity of PA metabolism and a multitude of compensatory mechanisms are invoked to maintain PA homeostasis [1], [38], [39], [40], [41], [42].
Transport is one of the main ways by which the intracellular PA content is regulated. The PA uptake is stimulated by the reduction of the intracellular PA content [10], [12], [13], [22], [42], [43], [44], [45]. PA uptake depends, in part, on the expression of cell surface proteoglycans (PGs), in particular those containing glycosaminoglycan heparan sulfate, highly charged polysaccharide, consisting of variably sulfated glucosamine residues and glucuronic or iduronic acid. The negatively charged carboxyl and sulfate groups can interact with the positive charges on the PAs with an affinity equal to or even higher than that for DNA. The inhibition of GAG synthesis or exogenous heparan sulfate reduces the uptake of exogenous PAs [45], [46], [47].
PA metabolism
Biosynthesis
PA biosynthesis is enhanced during growth and under the influence of growth-promoting stimuli, as in many diseases and cancer [1], [3], [4], [9], [10], [11], [12], [13], [14], [21], [22], [23], [32], [33], [34], [35], [36], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53]
PA synthesis occurs in the cytoplasm of cells of all tissues. In eukaryotic cells, three PAs are synthesized from two amino acids: L-methionine and L-ornithine (an amino acid that is a part of the urea cycle) [1], [5], [9], [10], [11], [12], [35], [43], [51], [52], [53].
The precursor of PAs is ornithine, an amino acid intermediate of the urea cycle, which is derived from arginine by the action of arginase (EC 3.5.3.1). Ornithine is then decarboxylated by ornithine decarboxylase (ODC, EC 4.1.1.17), a pyridoxal phosphate-dependent enzyme, the first and the rate-limiting enzyme in PA biosynthesis [1], [11], [54], [55], [56], [57]. ODC is characterized by an extremely short half-life, ranging from 15 to 25 min in eukaryotic cells, in comparison with many mammalian enzymes, the half-lives of which are more often expressed in days [1], [9], [10], [11], [12], [22], [54]. ODC activity is elevated in most human cancers [51]. The high level of ODC in tumor cells may be the cause of cell transformation, as it has been described as a proto-oncogene [1], [9], [10], [11], [12], [13], [21], [52], [54], [57].
The most important factor limiting ODC content appears to be antizyme (Az). This protein binds to ODC and increases its binding to the 26S proteasome. ODC is then degraded and Az is released, resulting in a further degradation of ODC [1], [40], [57], [58], [59], [60], [61], [62], [63].
Az is involved not only in ODC degradation, but also in the negative regulation of PA transport. Degradation is controlled by the pathway involving two proteins termed antizyme (Az) and antizyme inhibitor (AzI). Az can induce cell death associated with a rapid decline of intracellular PA contents [59]. Az inhibits the uptake of PAs and stimulates PA excretion [60]. As a result, Azs are regulated at the translational level by the level of PAs. AzI serves as a regulator; its action is based on its high affinity for Az, which is greater than the affinity Az has for ODC. AzI interferes with the binding of Az to ODC, thus rescuing ODC from degradation. The ability of Azs to degrade ODC, inhibit PA uptake and consequently suppress cellular proliferation suggests that Azs act as tumor suppressors, while the ability of AzIs to neutralize the Az function indicates their growth-promoting and oncogenic potential [57], [60], [61], [62], [63].
Produced putrescine is then converted to higher PAs, Spd and SP, via Spd synthase and Sp synthase, respectively [64]. Another important enzyme in the biosynthesis of PAs is S-adenosylmethionine decarboxylase (AdoMetDC), the key enzyme for Spd and Sp synthesis in mammals. It catalyzes the formation of decarboxylated S-adenosylmethionine (dcAdoMet), which is used as the aminopropyl donor. This is the sole function of the decarboxylated AdoMet. The aminopropyl group, formed by the decarboxylation of AdoMet, is conjugated with putrescine, by the action of Spd synthase, to form PA Spd. Spd is conjugated with another propylamino group, by the action of Sp synthase, to form polyamine Sp. The best known aminopropyltransferases are Spd synthase and Sp synthase [64], [65], [66], [67], [68], [69], [70], [71]. AdoMet is also the methyl source for many transmethylation reactions, including DNA and histone methylation. Thus, DNA methylation and PA synthesis depend on a common substrate, AdoMet [72], [73], [74], [75], [76]. As a consequence, changes in the cellular PA levels may affect the degree of DNA methylation [71], [72], [73], [76]. DcAdoMet is a poor methyl group donor; it starts inhibiting DNA methylation when its concentration exceeds that of AdoMet. At the dcAdoMet/AdoMet ratio of 5:1, there is very little methyl transfer [71], [72], [73], [74]. This is potentially very significant in the biological system. All known AdoMetDCs are members of the more limited class of decarboxylases that use a covalently bound pyruvate as the prosthetic group, which is a small number of pyruvoyl-dependent decarboxylases [64], [65], [66], [67], [68], [69], [70].
PA catabolism
The catabolic pathway of Sp and Spd is a two-step process involving, in the first reaction, Spd/Sp N′-acetyltransferase and in the second reaction, PA oxidase (PAO) [1], [22], [34], [40]. Sp and Spd are first acetylated by Spd/Sp N1-acetyltransferase (SSAT) and subsequently oxidized by PAO to produce Spd and putrescine, respectively (Figure 1) [1], [10], [72], [73], [74], [75], [76]. Acetylated Sp and Spd then move into peroxisomes where they are oxidized by PAO (EC 1.5.3.11), another enzyme of PA degradation [78]. SSAT (EC 2.3.1.57) participates in PA homeostasis by regulating PA catabolism and thus PA concentrations. Acetylation of PAs is a part of the catabolic process that allows the removal of PAs from the cell [76]. This enzyme catalyzes the formation of N1-acetylspermine and N1-acetylspermidine, less charged derivatives, by the transfer of an acetyl group from acetyl-CoA to the N1 position of Spd or Sp [74], [76]. Acetylation, as the means to diminish the number of charges on PA molecules, serves as an ordered mechanism to control DNA replication and transcription in vivo [79], [80]. Acetylation neutralizes the positive charge of the epsilon amino group of lysine residues, loosening the interaction between histones and the negatively charged DNA. The acetylation of PAs reduces their affinity for DNA and nucleosomes; thus, the helical twist of DNA in nucleosomes could be regulated by cells through acetylation. Histone and PA acetylations act synergistically to modulate chromatin structure [80], [81], [82]. The acetylating enzyme, SSAT, participates in PA homeostasis by regulating PA export and catabolism. SSAT may influence cellular metabolism by perturbing the content of acetyl-CoA and ATP, fatty acid precursor, and also the product of β-oxidation of fatty acids and the process of glycolysis [78], [83].
![Figure 1: Polyamine metabolism and methionine salvage pathway (Casero and Pegg [77], modified).MATtr, methionine adenosyltransferase; AdoMetDC, S-adenosylmethionine decarboxylase; ODC, L-ornithine decarboxylase; APAO, acetylpolyamine oxidase; PAO, polyamine oxidase; MTA, methylthioadenosine.](/document/doi/10.1515/pterid-2017-0012/asset/graphic/j_pterid-2017-0012_fig_001.jpg)
Polyamine metabolism and methionine salvage pathway (Casero and Pegg [77], modified).
MATtr, methionine adenosyltransferase; AdoMetDC, S-adenosylmethionine decarboxylase; ODC, L-ornithine decarboxylase; APAO, acetylpolyamine oxidase; PAO, polyamine oxidase; MTA, methylthioadenosine.
Many histone acetylases and deacetylases can be regulated by gene promoters and gene inhibitors, which, in turn, may be controlled by various PAs [82].
Acetylpolyamine oxidase (APAO) catalyzes the conversion of N1-acetylspermine to Spd and N1-acetylspermidine to putrescine. Acetylated PAs are generally the preferred substrates of APAO (EC 1.5.3.13), a flavin containing amine oxidase, the peroxisomal enzyme present in all vertebrate tissues and biological fluids [81]. PAO may also use nonacetylated Sp and Spd in vertebrate tissues [84], [85], [86], [87].
PAO, a flavine-adenine-nucleotide (FAD) containing enzyme, is also found in all vertebrate tissues and biological fluids. PAO represents the important enzyme of peroxisomes in the catabolic pathway of Sp and Spd. PAO is especially active toward Sp and N1-acetylated derivatives (N1-acetylspermine and N1-acetylspermidine), but less toward Spd. PAO catalyzes the oxidative deamination of Sp or Spd, producing Spd or putrescine, respectively, depending on the nature of the substrate. In its enzymatic activity PAO produces ammonia (NH3), corresponding amino aldehydes and hydrogen peroxide (H2O2). Malondialdehyde (MDA) and acrolein (CH2=CHCHO) are spontaneously formed from aminoaldehydes. The products of PAO activity are potentially toxic agents. Thus, PAO plays a role in triggering and/or participating in the progression of apoptosis and tumor appearance. The coupled responses of SSAT and PAO are responsible for the prevention of the over accumulation of PAs [20], [77], [88], [89], [90], [91], [92], [93], [94].
The acetylated PA products of the SSAT reactions, N1,N12-diacetylspermine (DiAcSpm) and N1,N8-diacetylspermidine (DiAcSpd), are excreted in human urine. Thus, DiAcSpm and DiAcSpd are minor components of human urinary polyamines [94].
Diamine oxidase (DAO)
Diamine oxidase (DAO, EC 1.4.3.6) is the enzyme that degrades putrescine, the main product of PA catabolism or interconversion. DAO, a copper-containing enzyme, catalyzes the oxidation of diamine putrescine to gamma-amino-butiric acid (GABA) or MDA [95], [96], [97], [98]. GABA, synthesized from putrescine, is well known to function as an inhibitory neurotransmitter in the central nervous system [99], [100].
Backconversion pathway of PAs
The decarboxylation and propylamine transferase reactions are practically irreversible. So, the entirely distinct system exists to convert higher PAs back to putrescine (Figure 1). This system utilizes two different enzymes, a cytosolic SSAT and a peroxisomal flavoprotein PAO [50].
5′-Methylthioadenosine
5′-Methylthioadenosine (MTA) is produced from AdoMet during the biosynthetic pathway of the PAs Sp and Spd. S-adenosylmethionine decarboxylase (AdoMetDC) catalyzes the formation of decarboxylated AdoMet, which is used as the aminopropyl donor in this reaction in which an amine acceptor (putrescine or Spd) forms PA (Spd or Sp). MTA formed in cellular processes is converted back to methionine in the methionine salvage pathway (Figure 1) [1], [50], [101].
MTA is a sulfur-containing nucleoside present in all mammalian tissues, including the prostate, liver, lung, spleen, kidney and heart. MTA is a potent inhibitor of cell proliferation. This compound contains methylthioribose-1-phosphate (MTR-1P) with adenine. MTA is normally rapidly degraded by MTA phosphorylase (MTAP). The action of MTAP starts the pathway by which the purine and methylthio-moieties of AdoMet, which are not used for PAs, are recycled via salvage pathways. Many tumors lack MTAP due to either the deletion or promoter hypermethylation of the MTAP gene. This lack of MTAP activity causes MTA accumulation. Spd-synthase and Sp-synthase are inhibited by MTA with Sp synthase being more sensitive [64], [65], [66], [67], [68], [69], [70]. MTAP is a well-known tumor suppressor and a regulator of purine and pyrimidine synthesis and metabolism. It influences numerous critical responses of the cell, including the regulation of gene expression, proliferation, differentiation and apoptosis. Several previous studies have shown that MTAP could be a prognostic marker in multiple cancer types [100], [101], [102], [103], [104], [105], [106]. MTAP is a gatekeeper which controls the balance between the de novo synthesis and the purine salvage synthesis, the folate cycle and the regulation of DNA methylation status. The loss of MTAP function leads to tumorigenesis and correlates with the survival of patients [103], [104], [105], [106], [107]. The hypermethylated state of promoter is the major modification of MTAP activity [106].
PA functions
Recent studies have identified that PAs have a number of key area effects on cellular metabolism [13]. But, despite several decades of intensive research work, their exact physiological functions remains obscure [108].
PAs have a multitude of functions affecting cell differentiation, proliferation, or cell growth and development [12]. At physiological pH, PAs carry a positive charge on each nitrogen atom; as polyanions they interact with nucleic acids, RNA and DNA, and proteins, glycoproteins and phospholipids in cell membranes. PA interaction with nucleic acids has been shown to affect the stability of double-stranded DNA; at physiological concentration, PAs can condense DNA and stabilize DNA compact forms [8], [24], [27], [28], [109], [110], [111]. These interactions influence the rate of biochemical reactions. The acetylation of PAs seems to be an important mode of PA-chromatin interaction regulation. Purified histone acetyltransferase (HAT) also possesses PA acetylation activity; thus, histones and PA acetylation may occur in tandem to regulate DNA replication and transcription [83].
Most PAs exist as a PA-RNA complex, and this complex influences protein synthesis. PA-mediated effects on RNA are frequently distinct from those of divalent cations (i.e. Mg2+), confirming their roles as independent molecular entities which help drive RNA-mediated processes [27]. By binding to DNA and RNA, PAs influence protein synthesis by the regulation of gene transcription and translation; they regulate translation both at the initiation and at the elongation steps. The group of genes whose expression is enhanced by PAs at the level of translation has been referred to as a “polyamine modulon” [9], [10], [11], [12], [34], [35], [111], [112], [113], [114], [115], [116].
The primary function of PAs, Spd and Sp, in mammalian cells is in translation [3], [14]. Spd participates in the synthesis of eukaryotic initiation factor 5A (eIF5A), serving as the source of hypusine by the enzyme deoxyhypusine synthase [14], [112], [113], [114], [115], [116], [117]. At the global level, PAs may regulate translation via hypusination of the putative translation factor eIF5A, the only protein that contains the unusual Spd-derived amino acid residue hypusine, which is essential for its biological activity [34], [35], [114], [115], [116], [117]. The requirement of eIF5A, which was originally suggested to function as the translation initiation factor, for cell growth raises the possibility that eIF5A hypusination may represent the major or even the entire requirement of PAs for cellular proliferation [14], [113], [114], [115]. But, Tomitori et al. [91] demonstrated that both eIF5A and PAs influenced cell growth, but in an independent manner. The decrease in either active eIF5A or PAs inhibited cell growth, indicating that eIF5A and PAs were independently involved in cell growth [115], [116], [117].
Also, PAs influence protein synthesis by the correct assembly of the ribosomal subunits [37], [38], [39]. PAs are repressors of transcription in vivo [14], [118]. They influence the formation of compact chromatin [118]. One role of histone hyperacetylation is to antagonize the ability of PAs to stabilize the highly condensed states of chromosomal fibers [33], [119]. They bind stronger AT-rich DNA compared to the GC-rich DNA and the binding varies depending on the charge on the PAs (Sp, Spd and putrescine) [33], [110].
PAs can interact with PGs with equal to or even higher affinity than that of DNA [5]. These highly charged polysaccharides consist of variably sulfated glucosamine residues and glucuronic or iduronic acids. The negatively charged carboxyl and sulfate groups can interact with the positive charges on PAs [5], [45], [46], [47], [48], [110].
PAs, especially Spd, affect lipid metabolism. They are present in mast cell secretory granules and indicate an essential role of these polycations during the biogenesis and homeostasis of these organelles. Mast cell secretory granules contain highly sulfated serglycin PG; PAs interact with PGs [120]. Lipid metabolism is a strong regulator of health and lifespan. Spd is a key factor in the process of adipogenesis. SSAT may influence cellular metabolism by perturbing the content of acetyl-CoA and ATP, fatty acid precursor, and also the product of β-oxidation of fatty acid and the process of glycolysis [74], [78], [83], [88]. The changes in the lipid profile will modulate membrane fluidity and lead to oxidative damage, as well as signaling. PA levels decrease with age in many organisms. This decrease could play a part in the cellular aging phenotype [120], [121], [122], [123].
PAs may play a direct and crucial role in cellular immunity and may be involved not only in inflammatory processes, but also in cytocidal activities. PAs could be considered as natural immunosuppressive factors. The immune function in cancer patients is suppressed; PAs represent one of the causative factors of immune suppression. Immune cells in an environment with increased PA levels lose anti-tumor immune functions. Increased blood PA levels, often observed in cancer patients, have negative impacts on patient prognosis and are associated with tumor progression [1], [3], [9], [13], [124], [125], [126].
PAs are potential anti-inflammatory agents. They have anti-inflammatory activity in acute and chronic inflammation, which can be attributed to their anti-oxidant and/or lysosomal stabilization properties [127], [128], [129], [130], [131]. The endogenous Sp normally inhibits the innate inflammatory response by restraining macrophages [126].
The association between inflammation and cancer has been illustrated by numerous epidemiologic and clinical studies [127], [128], [129], [130], [131]. The increased PA levels in cancer tissues and in blood may be one of the factors that hinder the immune function of cancer patients [127]. The increased blood Sp levels may be an important factor in the suppression of the anti-tumor immune cell function [132].
The PA levels in serum and in urine of healthy human beings are age related, declining progressively with increasing age [123].
PAs and cancer
PAs, putrescine, Spd and Sp, play an essential role in the proliferation and development of cancer cells. There is an enormous body of evidence for the important role of PAs in cancer. Cancer cells are rich in PAs [1], [2], [3], [4], [11], [21], [23], [51], [52], [93], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144]. PA levels are elevated in organs and tissues, as well as in the blood and urine of cancer patients due to the increased synthesis and active intercellular transport in cancer cells. The high levels of intracellular PAs promote HAT activity, resulting in chromatin hyperacetylation and the facilitation of tumor growth. Many histone acetylases and deacetylases can be regulated by gene promoters and gene inhibitors, which, in turn, may be controlled by various PAs [82]. Increased PA concentrations in tissues and organs correlate with diseases of neoplastic origin. The exact role of PAs in cancer is still unclear; it is likely that their high levels in cancer cells can help these cells maintain their proliferation capacity [21], [93], [140], [141], [142], [143], [144].
PAs are important for gene expression due to their ability to bind nucleic acids and proteins [1], [2], [3], [4]. They are gene-specific repressors of transcription in vivo, and one role of Gcn5p HAT is to antagonize PA function. PA and histone acetylations act synergistically to modulate the chromatin structure [118], [119]. In the presence of the increased amount of Sp, DNA transcriptional activity is enhanced [145].
The molecular linkages of PAs to signal transduction and oncogene/cancer suppressor gene expressions in various cell types have been reported. PA depletion and the inhibition of eIF5A hypusination inhibit cellular proliferation [116]. Elevated intracellular PA levels promote histone acetylation in proliferating cells, suggesting a mechanism by which altered PA biosynthesis contributes to the aberrant expression of genes, facilitating tumor growth [77], [81]. The dysregulation of cellular PAs is associated with various pathological conditions, including cancer [1], [2], [6], [146], [147], [148], [149]. A continuous supply of PAs is required for cancer cell proliferation [6], [132], [134], [143], [144], [147], [148], [149], [150]. PAs should be clinically utilized to track tumor evolution and tumor response to therapy in patients at high risk [21], [23], [144]. The elevated levels of PAs have been associated with brain tumors, epithelial, breast, colon, lung, prostate and skin cancers, where the altered levels of rate-limiting enzymes in both biosynthesis and catabolism have been observed [75], [77], [80], [149], [150], [151], [152], [153], [154], [155]. The enhanced levels of PA biosynthetic enzymes, ODC and AdoMetDC, are often associated with hyperproliferation and cancer. The aberrant expression of ODC plays a causal role in tumorigenesis. ODC activity is higher in cancer tissues than in normal surrounding tissues. ODC has long been known as a marker of carcinogenesis and tumor progression [150], [151], [152], [153], [154], [155]. Human breast cancer cells overproducing AdoMetDC (~five-fold) manifest reduced ODC, while SSAT is variably increased [152]. The enhanced proliferation in colon cancer cells is associated with increased AdoMetDC activity. AdoMetDC might be a preferable target for therapeutic attempts to impair growth by reducing intracellular PA pools in colon cancer [153]. The total PA content in breast cancer tissues is higher than in benign breast diseases and correlates well with ODC activity [153], [155]. Thus, the ornithine-derived putrescine plays a key role in tumor proliferation [93], [156].
The PA-hypusine axis is a new tumor suppressor network regulating apoptosis [157], [158]. Among the new tumor suppressors, there are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two molecules associated with hypusine.
PAs stimulate the expression of a variety of genes, including many implicated in cell proliferation. Tumor necrosis factor-α (TNF-α) can lead to the induction of NF-κB signaling with a concomitant increase in SSAT expression in A549 and H157 non-small cell lung cancer cells [75]. SSAT is increased in tumor tissue, whereas PAO is decreased [11]. PAO activity is significantly lower in the neoplastic tissue than in the surrounding mucosa in human colorectal cancer. The changes in PAO correlate with prognostic factors, and this enzyme activity decreases as tumor histological grade increases [11], [140]. Also, the significant elevation of DAO activity is in positive correlation with neoplastic growth [97], [159].
The evidence indicates that DiAcSpm and DiAcSpd are promising novel tumor markers. The urinary excretion of these PA derivatives is increased in association with every type of cancer [94]. Remission is usually accompanied by the normal level of these compounds. Thus, they deserve more intensive study, including a study of their biochemistry and metabolism [11], [93].
Hypoxia, a common condition in cancer tissues, exerts a strong pressure on cells to separate from the tumor cluster and migrate into circulation [160]. Tsujinaka et al. [147] reported that cancer cells under hypoxia lost the regulation of PA homeostasis and increased PA uptake from surrounding tissues [160], [161], [162]. Increased PA intake accelerates the growth of established tumors [163], [164], [165]. Cells can take up PAs from extracellular sources, such as food and intestinal microbes [163]. Luminal PAs are crucially involved in the normal and neoplastic growth of the gut. The major sources of exogenous PAs come from the diet and luminal bacteria. Dietary PAs are taken up by the intestinal tract and enter the systemic circulation [164], [165], [166]. Either produced by actively proliferating normal or cancer cells, or absorbed from the gastro-intestinal tract (food and colonic microfloral population), circulating PAs could favor, in vivo, malignant cell proliferation [163], [166]. On the other hand, in cancer patients, reduced PA dietary intake has been shown to be beneficial on the quality of life [165].
PAs have been attributed as markers of neoplastic proliferation in the colon. Dietary PAs have a major role in colorectal adenoma risk assessment. These findings would confirm a previously unrecognized, modifiable dietary risk factor for colorectal adenoma [151], [164], [165]. PAs have a preferential effect in controlling nuclear proto-oncogene expression (myc, jun and fos), but the preferential role of each of the PAs on proto-oncogene expression has not been explored. The increased PA availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells – “anti-tumor immune functions” [132], [134], [140], [141].
Biochemistry of folates and their function
Biochemistry
Folic acid, folacin or pteroylglutamic acid, is a water-soluble vitamin. The name folic acid is derived from the Latin word folium, meaning “leaf”, as it is found in many leafy plants. The best folate sources in the diet are green leafy vegetables as well as animal liver and kidney [166], [167], [168], [169]. Mammalian cells are devoid of the enzymatic capacity for folate biosynthesis and are absolutely dependent on folate uptake from exogenous dietary sources. Thus, the intestine plays a central role in regulating body folate homeostasis. The primary deposits of folate are the liver and kidney [168]. Similarly, the kidneys play a pivotal role in regulating body folate homeostasis by reabsorbing the filtered vitamin, thus preventing its loss by urine [167], [168], [169]. Folic acid refers to the oxidized synthetic compound used in dietary supplements and fortified food, while folate occurs naturally in food. It is well established that an adequate folate intake from the consumption of folate-rich foods is essential for health [168].
Folate coenzymes are specifically concerned with biochemical reactions, involving the transfer and utilization of the single carbon (C1) moieties, such as methyl-, methylene-, methenyl-, formyl or formimino-groups to various substrates in a variety of enzymatic reactions that are intimately related to the synthesis of DNA, RNA, proteins and phospholipids (lecithin and sphingomyelin) and to the metabolism of several amino acids, including methionine and others, cell division or red blood cell formation. Increased amounts of folate are required for the growth and reproduction of all body cells during periods of rapid cell regeneration and growth, such as cancer cells [168], [169].
The roles of folates
Folate is important for the prevention of diseases, such as neural tube defects (NTDs) and cardiovascular diseases [170], [171], [172], [173], [174], [175], [176], [177], [178], [179], [180], [181], [182], [183], [184]. During periods of rapid cell regeneration and growth, such as in cancer cells, increased amounts of folate are required. One-carbon metabolism is one of the metabolic pathways which have been successfully targeted in oncology. AdoMet is used for PA biosynthesis by the transfer of the propylamine moiety, and also as a methyl donor for widely biological methylation reactions [49], [71], [185], [186], [187], [188], [189]. Folate is necessary for the synthesis of methionine, for de novo purine synthesis and de novo synthesis of pyrimidine – thymidylate from deoxyuridylate. In mammalian cells, the de novo synthesis of thymidylate from deoxyuridylate is a rate-limiting step for DNA synthesis and requires 5,10-methylene tetrahydrofolate as the coenzyme [168], [169], [171], [172], [173], [174].
The methylation of DNA plays an important role in the control of gene expression and is critical during cell differentiation. Aberrations in DNA methylation have been linked to the development of cancer [190], [191], [192], [193], [194], [195], [196], [197], [198]. However, the intervention trials with high doses of folic acid have not generally shown any benefit on cancer incidence. On the other hand, it is possible that folate depletion manifests through disturbances in normal DNA, and possibly RNA, maybe through PA metabolism, producing its pro-carcinogenic effects [190], [191], [195], [196], [197].
Methionine pathways depend not only on the folate coenzyme (5-methyltetrahydrofolate), but also on coenzyme of vitamin B12 (Figure 2). The folate coenzyme plays a crucial role in methionine biosynthesis [185], [186], [187], [188], [189], [190], [191]. Thus, folate (and/or vitamin B12) deficiency can result in the decreased synthesis of methionine [192].
![Figure 2: Methionine metabolic pathways (Deacon et al. [170], modified). The folate coenzyme plays a crucial role in methionine biosynthesis. Methionine has many functions in the human body.](/document/doi/10.1515/pterid-2017-0012/asset/graphic/j_pterid-2017-0012_fig_002.jpg)
Methionine metabolic pathways (Deacon et al. [170], modified). The folate coenzyme plays a crucial role in methionine biosynthesis. Methionine has many functions in the human body.
PAs and folates are interconnected by methionine
Folates participating in methionine metabolism have a profound function in PA biosynthesis. Together with vitamin B12 and vitamin B6, methionine is the principal precursor of Spd and Sp [1], [49]. The overaccumulation of PAs induces apoptosis and cell malignant transformation, whereas PA depletion has been shown to inhibit cell proliferation [28]. The administration of folic acid to hepatectomized animals (30%) resulted in diminution of PAO activity in the regenerating rat liver tissue after hepatectomy [193]. The supplementation of experimental animals with vitamin B12 alone or together with folic acid increased the Spd and Sp levels in the rat liver. At the same time, the supplementation of experimental animals with vitamin B12 together with folic acid caused the decrease of PAO activity. Our experimental results indicated the importance of folic acid and cobalamin in PA metabolism [194].
Mild folate deficiency influences PA synthesis that occurs in all living organisms. Bistulfi et al. [195] found a significant correlation between PA biosynthesis and the amount of folate required to sustain cell line proliferation. These data demonstrate that PA biosynthesis is the critical factor in determining sensitivity to folate depletion and may be particularly important in the prostate, where the biosynthesis of PAs is characteristically high due to its secretory function. But, the interdependency of the folate and PA pathways has not yet been studied enough [196].
DNA methylation and cancer
The connection between PAs and nucleic acids appears crucial for the cellular functions of PAs. The normal mammalian development is dependent on DNA methylation [173], [174], [185], [190], [191]. The methylation of DNA by S-adenosyl-L-methionine is crucial for the regulation of gene expression and is a potentially mutagenic reaction [71], [81], [199], [200], [201], [202], [203], [204], [205], [206], [207], [208], [209], [210], [211], [212], [213], [214], [215], [216], [217], [218], [219], [220], [221], [222]. Cancer is thought to arise from DNA damage and an inappropriate expression of critical genes [184], [190]. The modulation of DNA methylation in response to folate has been demonstrated [203], [204].
PA synthesis and DNA methylation depend on a common substrate, AdoMet. As a consequence, changes in the cellular PA levels may affect the degree of DNA methylation [173], [193], [223].
DNA and histones are the targets for covalent modifications. The amino-terminal tails of the histone proteins protrude from the nucleosome core and are the subject of the diverse array of post-translational modifications that include acetylation, methylation and others. DNA methylation and histone acetylation are two of the best conserved chromatin modifications throughout eukaryotes and they are interconnected [186], [187], [188], [189]. These modifications induce significant changes in the genetic function in living cells [147], [189], [196], [197], [198], [199], [200], [201], [202], [203], [204], [205], [206], [224], [225].
All DNA aberrations enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes [186], [189], [206], [207], [208]. DNA methylation is directly involved in the suppression of transcription. Hypermethylation represses the transcription of the promoter sections of tumor suppressor genes, leading to gene silencing [174], [203], [206], [209], [210], [211], [212]. The inactivation of tumor suppressor genes by the hypermethylation of promoter regions is associated with a variety of human neoplasms and tumors. The hypermethylation of CpG islands associated with the tumor suppressor genes is the first manifestation of cancer [206], [207], [208], [209], [210], [211], [212].
DNA modification is one of the epigenetic phenomena, an alteration in gene expression without any change in the nucleotide sequence. DNA methylation is considered to be a stable modification associated with the epigenetic silencing of genomic loci and maintained through cellular division [173]. DNA methylation in eukaryotes involves the addition of a methyl group to the carbon 5position of the cytosine ring. This reaction is catalyzed by DNA methyltransferase, which transfers a methyl group from AdoMet in the direction of the sequence 5′-CG-3′, which is also referred to as a CpG dinucleotide, named CpG islands. DNA methyltransferases (DNMTs) comprise a family of nuclear enzymes that catalyze the methylation of CpG dinucleotides, resulting in an epigenetic methylome distinguished between normal cells and those in a diseased state, such as cancer. Tumorigenic cells contain higher levels of methylating capacity than nontumorigenic cells; the literature data show that methyltransferase activity was significantly higher in tumorigenic than in nontumorigenic cells [204], [205]. PAs, Spd and to a lesser extent Sp, control DNA methylation. Sp and Spd (but not putrescine) selectively inhibit cytosine-DNMT activity [145]. Approximately 4% of the genomic DNA is hypermethylated primarily in the form of 5-methylcytosines in CpG dinucleotides [205]. In normal human cells, the majority of CpGs are methylated. The methylation of DNA at CpG dinucleotides represents some of the most important epigenetic mechanisms involved in the control of gene expression in vertebrate cells. Large stretches of DNA can become abnormally methylated in cancer [211], [212], [213], [214], [215], [216], [217], [218].
The hypermethylation consistently observed in CpG islands, therefore, represents a change in 5-methylcytosine distribution across the genome rather than an overall increase in the total amount of methylation. The hypermethylation of promoter regions of DNA inactivates tumor suppressor genes; this is associated with a variety of human neoplasms and tumors [200], [201], [202], [203], [204], [205], [206], [207], [208], [211], [212], [213], [214], [215], [216], [217], [218], [219].
Chromatin exists either in a transcriptionally active state in which histones are acetylated or in a repressed state in which histones are not acetylated [145], [220]. The structural modifications of DNA and histones, such as methylation and acetylation, induce significant changes in the genetic function in living cells [222], [226], [227], [228].
Hypomethylation has also been identified as a cause of oncogenesis. Folate deficiency causes a shortage in nucleotides and might lead to genome instability and DNA mutations. The hypomethylation of CpG islands often leads to gene reactivation [229], [230]. Folate deficiency causes massive incorporation of uracil into human DNA (4 million per cell) and chromosome breaks [229], [230]. The likely mechanism is the deficient methylation of dUMP to dTMP and the subsequent incorporation of uracil into DNA. Such breaks could contribute to an increased risk of cancer [193], [229], [230].
Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences [190], [223], [231], [232]. DNA methylation and demethylation are considerably more dynamic than previously thought and may be involved in the repression and derepression of gene activity during the lifespan of a cell [217], [218]. In general, DNA methylation represses transcription, and the loss of methylation is associated with gene activation [192], [193], [193], [194], [195], [196], [197], [198], [199], [200], [201], [202], [203], [204], [205], [206], [207], [208], [209], [210], [211], [212], [224], [225]. There is considerable evidence that aberrant DNA methylation plays an integral role in oncogenesis [186], [187], [188], [189], [190], [191], [195], [196], [197], [198], [199], [200], [203], [204], [205], [206], [207], [208], [209], [210], [211], [223], [224], [225].
Histone acetylation and methylation are two major modifications that function as a specific transcription regulator and are interconnected [220], [221], [222]. DNA methylation takes part in this process by inducing decreased levels of chromatin acetylation [229]. Also, the methylation of messenger RNAs (mRNAs) at 5′-terminal cap plays an important role in mRNA export from the nucleus, efficient translation and the protection of the integrity of mRNAs [186], [195].
Two classes of enzymes reversibly control the acetylation level of histones: HATs and histone deacetylases (HDACs). In general, transcriptional activators recruit HATs, whereas transcriptional repressors and co-repressors associate with HDACs [215].
The PA and histone acetylations act synergistically to modulate the chromatin structure [12], [80]. The aberrations in chromatin remodeling are associated with cancer formation [21], [80], [233], [234], [235]. PAs enhance the action of HATs either directly or indirectly [145]. HAT also possesses PA acetylation activity; thus, histone and PA acetylations may occur in tandem to alter the structure/function of the nucleosome, thereby regulating DNA replication and transcription. The acetylation of a PA is important for gene expression due to their ability to bind to nucleic acids and proteins [8], [224]. One role of the Gcn5p histone acetyltransferase is to antagonize PA function [118], [119], [196]. Hypoacetylated chromatin domains are often correlated with transcriptional inactivity [81], [82], [119]. Many histone acetylases and deacetylases can be regulated by gene promoters and gene inhibitors, which, in turn, may be controlled by various PAs [93]. The contribution of PAs to transcriptional regulation in vivo may also be controlled by the balance between histone acetylation and deacetylation reactions. PAs have linkages to the actions of epithelial growth factor, transforming tumor growth factor β, TNF-α, and hepatocyte growth factor and to several oncogenes including NF-κB, c-myc, c-jun, and c-fos and cancer suppressor genes, including p53 [93].
The PA amount in the cells, especially Sp, may affect the transcriptional activity of DNA. In the presence of an increase in the Sp concentration, transcriptional activity is enhanced [119]. Elevated intracellular PA levels increase histone acetylation in proliferating cells, suggesting the mechanism by which altered PA biosynthesis contributes to aberrant expression of genes, facilitating tumor growth [93].
Acetylation neutralizes the positive charge of the epsilon amino group of lysine residues, loosening the interaction between histones and the negatively charged DNA. The acetylation of PAs reduces their affinity for DNA and nucleosomes; thus, the helical twist of DNA in nucleosomes could be regulated by cells through acetylation [81], [82], [93], [119].
Acetylation as the means of diminishing the number of charges on PA molecules serves as an ordered mechanism to control DNA replication and transcription in vivo. One of the major functions of histone acetylation is to open chromatin to allow transcription factors to gain access to the regulatory elements in DNA [82].
Sp seems to play important roles in inhibiting age-associated and PA-deficient induced abnormal gene methylation, as well as pathological changes, including tumorigenesis [161].
PA and folates in carcinogenesis
The impact of folate on health and disease, particularly pregnancy complications and congenital malformations, is without doubt [167], [168], [169], [175], [176], [235], [236]. It is well established that adequate folate intake from the consumption of folate-rich foods is essential for health [167], [168], [169]. However, an entirely protective role of folate against carcinogenesis has been questioned. Over the past few years, the world population has been exposed to the significant increase in folate intake, for which no data on safety exist. Increased folate intake may be associated with unexpected adverse effects [237], [238], [239], [240], [241], [242], [243]. Although folic acid is generally regarded as safe, folic acid fortification may have adverse effects. Maintaining adequate folate levels may be important in lowering the risk of cancer. Recent data indicate that an excessive intake of synthetic folic acid (from high-dose supplements or fortified foods) may increase human cancers by accelerating the growth of precancerous lesions. Inadequate folate intake contributes to genome instability and chromosomebreakage that often characterize cancer development [190], [191], [199], [203], [238].
When the intake of folic acid is higher than 400μg/day, unmetabolized folic acid appears in peripheral blood and this form of folic acid may have adverse effects. The presence of unmetabolized folic acid (PteGlu) in blood is one of the etiopathogenetic causes of colorectal cancer [242], [243]. The biochemical and physiologic consequences of the increased exposure to circulating folic acid are unknown, but it is very important to understand the effects of chronic exposure to circulating folic acid [238], [239], [240], [241], [242], [243], [244], [245], [246].
Folate has a dual effect on cancer: protecting against cancer initiation, but facilitating the progression and growth of preneoplastic cells; a low folate status might inhibit colorectal carcinogenesis and a high folate status may promote colorectal carcinogenesis. These initial dual effects of folate may be explained by their function in the nucleotide synthesis. Rapidly proliferating tissues, including tumors, have an increased requirement for nucleotides; many cancers up-regulate folate receptors, and antifolate drugs are efficacious in cancer treatment [240], [241].
Data from the majority of human studies suggest that a high dose of folic acid supplementation may enhance the risk of carcinogenesis in certain circumstances [189], [206], [242], [243], [244], [245], [246], [247], [248], [249], [250]. Folic acid supplementation may enhance the development and progression of already existing, undiagnosed premalignant and malignant lesions. Folate supplementation can be preventive before a neoplastic transformation, but can act as a growth promoter in neoplastic cells [203], [246].
The possibility of the cancer-promoting effect of folic acid supplementation needs to be considered by a careful monitoring of the long-term effects of folic acid fortification on a vast majority of the population, who intake folic acid from fortified products and are not at risk of NTDs [203].
Conclusion
We believe that the understanding of the metabolism of PAs and their roles in cellular metabolism, in physiological and pathological circumstances, could help in solving the problem of the folate supplementation-cancer relationship. Further study is necessary to clarify the interactions between folate and PA metabolism and to determine whether PAs are involved in the damaging effects of folate oversupplementation.
Conflict of interest statement: The authors have declared no conflicts of interest.
Funding: This study was funded by Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja, (Grant/Award Number: III41018).
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- Frontmatter
- Reviews
- Photosensitization of peptides and proteins by pterin derivatives
- Polyamines, folic acid supplementation and cancerogenesis
- Mini review
- Medical significance of simultaneous application of red blood cell distribution width (RDW) and neopterin as diagnostic/prognostic biomarkers in clinical practice
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- Molecular architecture of pterin deaminase from Saccharomyces cerevisiae NCIM 3458
- Quantitative analysis by flow cytometry of green fluorescent protein-tagged human phenylalanine hydroxylase expressed in Dictyostelium
- Age-dependance of pteridines in the malaria vector, Anopheles stephensi
- Seasonality of blood neopterin levels in the Old Order Amish
- Correlation of salivary neopterin and plasma fibrinogen levels in patients with chronic periodontitis and/or type 2 diabetes mellitus
- Positive association between Toxoplasma gondii IgG serointensity and current dysphoria/hopelessness scores in the Old Order Amish: a preliminary study
- Sleep onset insomnia, daytime sleepiness and sleep duration in relationship to Toxoplasma gondii IgG seropositivity and serointensity
- Concentrations of neopterin, kynurenine and tryptophan in wound secretions of patients with breast cancer and malignant melanoma: a pilot study
- Comparison of performance of composite biomarkers of inflammatory response in determining the prognosis of breast cancer patients
- Association of peripheral blood cell count-derived ratios, biomarkers of inflammatory response and tumor growth with outcome in previously treated metastatic colorectal carcinoma patients receiving cetuximab
- Neoadjuvant combination therapy with trastuzumab in a breast cancer patient with synchronous rectal carcinoma: a case report and biomarker study
Articles in the same Issue
- Frontmatter
- Reviews
- Photosensitization of peptides and proteins by pterin derivatives
- Polyamines, folic acid supplementation and cancerogenesis
- Mini review
- Medical significance of simultaneous application of red blood cell distribution width (RDW) and neopterin as diagnostic/prognostic biomarkers in clinical practice
- Original articles
- Molecular architecture of pterin deaminase from Saccharomyces cerevisiae NCIM 3458
- Quantitative analysis by flow cytometry of green fluorescent protein-tagged human phenylalanine hydroxylase expressed in Dictyostelium
- Age-dependance of pteridines in the malaria vector, Anopheles stephensi
- Seasonality of blood neopterin levels in the Old Order Amish
- Correlation of salivary neopterin and plasma fibrinogen levels in patients with chronic periodontitis and/or type 2 diabetes mellitus
- Positive association between Toxoplasma gondii IgG serointensity and current dysphoria/hopelessness scores in the Old Order Amish: a preliminary study
- Sleep onset insomnia, daytime sleepiness and sleep duration in relationship to Toxoplasma gondii IgG seropositivity and serointensity
- Concentrations of neopterin, kynurenine and tryptophan in wound secretions of patients with breast cancer and malignant melanoma: a pilot study
- Comparison of performance of composite biomarkers of inflammatory response in determining the prognosis of breast cancer patients
- Association of peripheral blood cell count-derived ratios, biomarkers of inflammatory response and tumor growth with outcome in previously treated metastatic colorectal carcinoma patients receiving cetuximab
- Neoadjuvant combination therapy with trastuzumab in a breast cancer patient with synchronous rectal carcinoma: a case report and biomarker study
