Advances in Preventive Medicine and Health Care (ISSN: 2688-996X)

review article

  PDF Download

A Lifestyle/Nutraceutical Program for Minimizing Colorectal Cancer Risk by Opposing β-Catenin Activity in Colonic Epithelium

Mark F. McCarty*1, Simon Iloki Assanga2, Lidianys Lewis Lujan2

1Catalytic Longevity Foundation, San Diego, CA, USA

2Department of Research and Postgraduate in Food, University of Sonora, Mexico

*Corresponding author: Mark F. McCarty, Catalytic Longevity Foundation, San Diego, CA, USA

Received Date: 09 January, 2021; Accepted Date: 20 January, 2021; Published Date: 22 January, 2021

Citation: McCarty MF, Assanga SI, Lujan LL (2020) A Lifestyle/Nutraceutical Program for Minimizing Colorectal Cancer Risk by Opposing β-Catenin Activity in Colonic Epithelium. Adv Prev Med Health Care 4: 1023. DOI:


Up-regulated activity of β-catenin, which serves as a coactivator for TCF/LEF transcription factors and thereby promotes transcription of genes promoted cellular proliferation, opposing apoptosis, and aiding cellular migration, is known to be a key driver of colorectal cancer induction. An analysis of the molecular pathways influencing β-catenin activation indicates that lifestyle, pharmaceutical, and nutraceutical measures linked in epidemiology and rodent studies to decreased risk for this malignancy, are protective at least in part owing to a down-regulatory impact on β-catenin activity. Such measures include wholefood fiber-rich plant-based diets, ingestion of cruciferous vegetables, aerobic exercise training, daily low-dose aspirin, metformin therapy, and increased intake of vitamin D, calcium, and soy isoflavones. There is also reason to suspect that supplementation with high doses of folate and of biotin may oppose β-catenin activity and colorectal cancer induction via increased production of cGMP in colorectal epithelium, that the sesame lignin sesamol may likewise provide protection in this regard by targeting colonic NOX1 activity, that quercetin or more soluble derivatives thereof may decrease colorectal cancer risk via inhibition of the kinase CK2, and that astaxanthin may decrease this risk by increasing plasma adiponectin and via antioxidant activity. Scope for prevention of colorectal cancer – still the number 2 cancer killer despite screening strategies that can often detect it in a surgically curable stage – may be quite substantial.


Colorectal cancer prevention; Beta-catenin; Aspirin; Metformin; Vitamin D; Calcium; Isoflavonees, Folate, Biotin, Sesamol; Quercetin; Astaxanthin

Targeting β-Catenin for Prevention of Colorectal Cancer

Despite the availability of clinical strategies that are reasonably effective for detecting it in a surgically curable stage, colorectal cancer remains the number 2 cause of cancer mortality in the Western world. A great deal of evidence indicates that the proproliferative, anti-apoptotic effects of excessive, uncontrolled betacatenin activity play a key role in the induction and progression of a large majority of colorectal cancers [1,2]. The thesis of this essay is that factors known to either promote or oppose the induction of colorectal cancer do so in large part via modulation of beta-catenin activity – and that a lifestyle/nutraceutical regimen designed to oppose this activity may have considerable potential for colorectal cancer prevention.

Beta-catenin acts as a coactivator for the T-cell factor/ lymphoid enhancer factor (TCF/LEF) class of transcription factors [3,4]. When nuclear levels of β-catenin are low, the corepressor groucho protein binds to TCF, such that TCF functions as a repressor of genes whose promoter it binds to. But when nuclear levels of β-catenin rise, the latter displaces groucho in binding to TCF, and TCF then promotes the transcription of these genes. The genes whose transcription is promoted by the TCF/β-catenin complex code for a number of proteins that promote cell proliferation, inhibit apoptosis, and degrade the extracellular matrix - proteins that promote cancerous transformation and metastatic behavior. These include c-myc, cyclin D1, survivin, and metalloproteinase-7 [1,5].

Mechanisms that Modulate β-Catenin’s Expression, Localization, and Coactivational Activity

In the absence of certain activating signals, most of the β-catenin in the cell binds to cadherins at the plasma membrane surface [6,7]. And much of the cytoplasmic β-catenin is tied up in a so-called “Destruction complex” which includes the proteins axin, adenomatous polyposis coli (APC), casein kinase-1a (CK-1a), and glycogen synthase kinase-3β (GSK-3β) [8]. After a “priming” phosphorylation of β-catenin by CK-1a on Ser45, GSK-3β then can phosphorylate it on Ser33, Ser37, and Thr41, which prepares it for ubiquitinylation and subsequent proteasomal degradation. These joint mechanisms cooperate to minimize nuclear β-catenin. In a very high proportion of colorectal cancers, loss-of-function mutations of APC preclude the formation of the destruction complex, such that ubiquitination-dependent proteasomal disposal of β-catenin is greatly compromised [9]. APC(Min/+) mice, which are heterozygous for loss of APC function, are highly prone to development of intestinal cancer, and are widely employed as a model of colorectal cancer induction [10].

Activated Akt can confer an inhibitory phosphorylation on GSK-3β, such that its ability to phosphorylate and prime for degradation β-catenin is suppressed; moreover, Akt can phosphorylate β-catenin at Ser552, which aids β-catenin’s translocation to the nucleus [11,12]. And β-catenin can be phosphorylated at both Ser552 and Ser675 by protein kinase A (PKA), the kinase activated by cAMP; these modifications stabilize β-catenin, promote its translocation to the nucleus, and enhance its interaction with TCF [13]. Hence, both Akt and PKA unleash β-catenin’s ability to promote gene transcription.

In addition, certain tyrosine kinases such as c-Src can phosphorylate β-catenin at Tyr654, which blocks its ability to bind to E-cadherin [14]. This modification also promotes nuclear translocation of β-catenin, as well as its ability to act as a coactivator for TCF [15,16].

Whereas cAMP, via PKA, acts to boost β-catenin’s activity, cGMP, acting via protein kinase G (PKG), has the opposite effect. PKG has been shown to lower cellular β-catenin levels and decrease its mRNA expression – possibly owing to suppressed transcription of the β-catenin gene CTNNB1 [17-21]. The mechanism whereby PKG achieves this still requires clarification. PKG can also decrease the nuclear interaction of β-catenin with TCF by boosting intra-nuclear levels of FOXO4, which competes with TCF for binding to β-catenin as a coactivator [22]. Colon epithelium expresses a guanylate cyclase 2C membrane receptor which generates cGMP in response to paracrine stimulation by the hormones guanylin and uroguanylin; this system is known to act as a tumor suppressor, and it tends to be lost or down-regulated during the process of colon carcinogenesis [23].

Physiologically important modulation of β-catenin activity is also mediated by estrogen receptor-β (ERβ), AMP-activated kinase (AMPK), and the kinase CK2 (formerly known as casein kinase-2). When activated via a ligand, ERβ migrates to the nucleus and suppresses β-catenin expression at the mRNA level; whether it binds to the CTNNB1 promoter has not been established [24]. AMPK likewise down-regulates β-catenin expression in colorectal epithelium; this is associated with a failure of Akt to confer an activating/stabilizing phosphorylation on Ser552 [25]. Recent studies suggest that this reflects AMPK-mediated inhibition of PI3K/Akt activity, and/or a direct binding of AMPK to β-catenin that may impede its interaction with Akt [25,26]. CK2, which is ubiquitously expressed, and over-expressed in colorectal cancer, promotes β-catenin stability and enhances its ability to enable TCF/LDF-mediated transcription [27-30]. CK2 confers a phosphorylation on Akt which appears necessary for the latter’s ability to phosphorylate and stabilize β-catenin [31,32].

As we will now see, this simple overview now prepares us to understand a range of practical strategies for suppressing colorectal cancer induction. These mechanisms are depicted in Figure 1.

Opposing Cox-2 Activity - Aspirin, Vitamin D, Antioxidants, and Fiber

Expression of cyclooxygenase-2 (COX-2) is elevated in about 85% of colorectal cancers, and about half of adenomas [33]. Constitutive COX-1 and inducible COX-2 are expressed in normal colorectal epithelium, and their joint expression is elevated in the normal colonic mucosa of patients who have previously developed colorectal cancer [34]. A key product of COX activity, prostaglandin E2 (PGE2), acts in an autocrine/paracrine fashion on colorectal epithelium via EP2 receptors to promote generation of cAMP via adenylate cyclase, and via EP4 receptors to stimulate PI3K/Akt activity [35]. Hence, PGE2 acts via both cAMP and Akt to boost β-catenin activity. (Conversely, beta catenin activity promotes transcription of the COX-2 gene [36].) This likely explains why regular use of NSAID drugs has been linked to lower risk for colorectal cancer [37,38]. In this regard, daily low-dose aspirin, which is relatively safe for use as a preventive strategy, has been found to notably lower risk for this cancer in a meta-analysis of large-scale lengthy randomized controlled trials; risk was about 25% lower in those who had taken daily low-dose aspirin for at least 5 years [39].

Colorectal epithelium expresses the 25-hydroxyvitamin D 1-alpha-hydroxylase (CYP27B1) activity required for conversion of circulating 25-hydroxyvitamin D to the active hormone calcitriol; it also expresses vitamin D receptors [40]. Hence, vitamin D’s hormonal activity within colorectal epithelium tends to vary directly with plasma levels of 25-hydroxyvitamin D. Notably, in a range of tissues, calcitriol has been shown to boost mRNA and protein expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the chief enzyme that catabolizes PGE2 to an inactive form [41,42]. Moreover, there is also evidence that vitamin D activity can suppress cox-2 expression, possibly because it induces expression of MAP kinase phosphatase-1, an antagonist of MAP kinase activities that activate the promoter of the COX2 gene [43-46]. Consistent with this analysis, vitamin D supplementation was shown to markedly lower the ratio of COX2/15-PGDH expression in the rectal mucosa of colorectal adenoma patients [47]. Notably, a meta-analysis of 15 case-control or cohort studies has found that risk for colorectal cancer is about one-third lower in the upper quantile as opposed to the lower quantile of plasma 25-hydroxyvitamin D [48].

Colitis notably increases risk for colorectal cancer, and oxidative stress both characterizes and promotes inflammation. Indeed, oxidative stress is likely to play a role in cox-2 induction during colorectal carcinogenesis, as it tends to boost the MAP kinase and NF-kappaB activities that drive cox-2 expression at the transcriptional level [49]. Colonic epithelium expresses the NOX1 isoform of NADPH oxidase [50,51]. Inhibition of NOX1 activity in a human colon cancer-derived cell line via apocynin, siRNA transfection, or the sesame lignin sesamol - which suppresses NOX1 mRNA expression in these cells - decreases COX-2 expression at the transcriptional level [52]. Moreover, dietary administration of sesamol suppresses intestinal polyp formation in APC(Min/+) mice. If this lignin were to become available as a nutraceutical, it might have potential as a chemopreventive agents for colorectal cancer.

The unconjugated bilirubin evolved by heme oxygenase activity functions as an inhibitor of certain NAPDH oxidase complexes, and its activity in this regard is mimicked by the phycocyanobilin chromophore richly supplied by certain cyanobacteria and blue-green algae - most notably spirulina, traditionally employed as a food in some cultures and now used as a nutraceutical [53-57]. However, the only study to evaluate bilirubin’s impact on NOX1 activity failed to demonstrate inhibition - whereas the carbon monoxide evolved by heme oxygenase activity was inhibitory [58]. Nonetheless, oral administration of phycocyanin, the algal protein to which phycocyanobilin is covalently attached, has been shown to suppress colon carcinogenesis in dimethylhydrazine-treated mice [59,60]. Perhaps this reflects its impact on NOX2-dependent NADPH oxidase activity in pro-inflammatory myeloid cells in the intestinal mucosa.

Phase 2 inducers, such as the sulforaphane provided by cruciferous vegetable, promote expression of a range of antioxidant enzymes via activation of the nrf2 transcription factor, and are thought to have important potential for colorectal cancer prevention [61]. In particular, they induce expression of heme oxygenase-1, which can inhibit NOX1 via generated carbon monoxide [58,62]. In APC(Min/+) mice that are further genetically modified to lack nrf2 expression, intestinal expression of cox-2 is enhanced, and intestinal tumorigenesis is notably up-regulated; conversely, administration of phase 2 inducers suppresses intestinal carcinogenesis in APC(Min/+) mice and mice treated with azoxymethane/dextran sodium sulfate [63-65]. These findings correlate nicely with epidemiological studies linking high intakes of cruciferous vegetables to decreased risk for colorectal cancer - as ratified in a meta-analysis [65,66]. The nutraceutical phase 2 inducer lipoic acid might likewise have protective potential in this regard [67-69] albeit its impact on colorectal cancer induction in rodents has so far received little if any investigation.

The carotenoid antioxidant astaxanthin - more effective than vitamin E for preventing membrane oxidation - shows protective effects in rodent models of colorectal cancer induction induced by dimethylhydrazine, azoxymethane, and dextran sodium sulfate; one of these studies reports suppression of COX-2 induction [70- 73]. These studies suggest that astaxanthin may have potential for prevention of inflammation-linked colorectal carcinogenesis.

Elevated Western risk of colorectal cancer - as compared to the much lower rates seen in the rural Third World - have suggested that low-fat, high fiber diets may confer protection from this cancer [74]. Curiously, prospective epidemiology has failed to establish a role for dietary fat in this regard, but high fiber diets do emerge as protective in prospective and case-control studies [75-77]. Diets rich in soluble fiber and/or “Resistant” carbohydrate provide substrate for the production of short-chain fatty acids such as butyrate by colonic bacteria [78]. These short-chain fatty acids serve as metabolic fuel for the colon epithelium, but they also activate the free fatty acid receptor 2 (FFAR2 - a.k.a GPR43) receptor expressed by these epithelial cells. Genetic knockout of this receptor boosts intestinal tumor yields in APC(Min/+) mice and in mice treated with the colon carcinogen azoxymethane [79]. Notably, FFAR2 is a seven-pass receptor capable of activating Gαi, which suppresses adenylate cyclase activation and hence lowers cellular levels of cAMP [80]. Hence, FFAR2 acts as a functional antagonist of the cancer-promoting activity of cox-2/PGE2.

Stimulating AMPK with Metformin, Berberine, and Vegan Diet

The ability of AMPK to decrease β-catenin activity helps to explain epidemiology pointing to lower risk for colorectal cancer in diabetics who use metformin as opposed to other antidiabetic medications [81-84]. The nutraceutical berberine, which like berberine can activate AMPK, and is widely used for management of type 2 diabetes in China, also appears to have potential for prevention of colorectal cancer [85-87]. Indeed, berberine reduces tumorigenesis in APC(Min/+) mice, and was shown to decrease risk for recurrence of colorectal adenoma in a multi-center doubleblind randomized controlled study [88,89].

The adipocyte-derived hormone adiponectin boosts AMPK activity in its target tissues - which include colonic epithelium; moreover, adiponectin knockout boosts colorectal carcinogenesis in fat-fed and in APC(Min/+) mice [90-92]. Obesity, most notably abdominal obesity, is associated with a markedly increased risk for colorectal cancer - as well as low plasma levels of adiponectin [93,94]. Epidemiological studies have concluded that low adiponectin levels are likely to play a mediating role in obesity’s impact on colorectal cancer risk (in contrast to the adipokine leptin) [95].

Whereas weight loss can boost adiponectin levels, adipocyte production of this factor is also boosted by fibroblast growth factor 21 (FGF21); indeed, increased adiponectin production appears to explain the favorable impact of FGF21 on insulin resistance and glycemic control in mice [96,97]. Hepatic production and plasma levels of FGF21 are boosted by dietary restriction of protein or of certain essential amino acids - a feature of low-protein plantbased (vegan) diets; indeed, a recent clinical study found that plasma FGF21 levels are about three-fold higher in vegans than in omnivores [98-100]. Hence, the increased FGF21 activity associated with vegan diets may act to lower colorectal cancer risk both by a rapid impact on adiponectin production, and by a longer term tendency to prevent or reverse obesity [98]. The ability of a low-protein diet to enhance plasma levels of adiponectin has been demonstrated in rats [101].

Although astaxanthin is typically thought of as an antioxidant, it can also act as a PPARα agonist, and supplemental intakes of 12-18 mg daily produce effects on serum lipid profile analogous to those of PPARα agonist drugs such as fenofibrate [102]. A key effect of PPARα agonists is to boost hepatic production of FGF21, which likely explains why astaxanthin supplementation has been found to increase plasma adiponectin levels [102-108]. Hence, astaxanthin supplementation has the potential to decrease colorectal cancer risk via up-regulation of adiponectin.

Vegan Diets and Exercise Training Down-Regulate IGF-I Activity

Moreover, FGF21 inhibits hepatic production of IGF-I, and plasma IGF-I levels tend to be lower in vegans and those eating lowprotein diets [98,109-111]. Colorectal epithelium is responsive to the pro-proliferative impact of IGF-I, and elevated IGF-I has been linked to increased risk for colorectal cancer [112,113]. IGF-I could be expected to boost β-catenin activity via PI3K-Akt signaling. Effective IGF-I activity is decreased by plasma IGFBP-1, which is decreased by the hyperinsulinemia associated with obesity. Aerobic exercise training, in the short term, can increase plasma IGFBP-1 by improving peripheral insulin sensitivity and thereby down-regulating insulin secretion, and in the longer term by opposing inappropriate weight gain [114]. Not surprisingly, it is associated with decreased risk for colorectal cancer [115].

Diets rich in heme iron have been linked to increased risk for colorectal cancer, possibly because this well absorbed form of iron may promote pro-mutagenic oxidative damage [116-118]. Vegan or vegetarian diets do not contain heme iron. Although plant-based diets can be rich in iron, non-heme iron has not been associated with increased risk for colorectal cancer, and its absorption is regulated in line with physiologic need [119].

Overall, these considerations suggest that whole-food fiberrich quasi-vegan diets can work in various complementary ways to lower colorectal cancer risk - as borne out by global epidemiological experience; age-adjusted risk for colorectal cancer used to be at least several-fold lower in the rural Third World as compared to Western nations, as stressed in the writings of Denis Burkitt and Hugh Trowell [119].

Protective Mechanisms of Calcium, Magnesium, Soy Isoflavones, and Quercetin

The hydrophobic bacterial bile acid metabolite deoxycholic acid (DCA) stimulates proliferation of colon epithelium, exerts mutagenic effects on colon epithelial cells in vitro, and acts as a tumor promoter in rodent models of intestinal carcinogenesis [120-123]. Increased serum levels of DCA have been reported in men with colonic adenomas [124,125]. DCA activates β-catenin signaling in colon cancer-derived cell lines [120,126,127]. This effect is associated with a loss of E-cadherin binding to β-catenin that may reflect activation of c-Src [128,129]. There is considerable epidemiological evidence that high calcium intakes, whether via diet or supplementation, notably reduce risk for colorectal cancer [130-132]. This appears likely to reflect the ability of calcium to form unabsorbable complexes with DCA such that DCA’s uptake by colonic epithelium is suppressed and fecal loss of DCA rises [133,134]. It is conceivable that magnesium has a comparable effect, as there is evidence that higher intakes of magnesium are also associated with decreased colorectal cancer risk – albeit an effect of lesser magnitude than that of calcium [131,135,136]. Including some magnesium while supplementing with calcium may be prudent, as high-dose calcium supplementation in the context of low-magnesium diets may have a negative impact on magnesium status [137].

With respect to the ability of activated ERβ to suppress β-catenin expression, it is notable that, in “physiological” doses obtainable from ample ingestion of soy products, the soy isoflavone genistein acts as a selective agonist for ERβ, with minimal impact on “feminizing” ERα [138]. S-equol, a metabolite of the isoflavone daidzein produced by colonic bacteria, can also act as a selective agonist for ERβ [139]. These facts may explain the lower risk for colorectal cancer associated with high intakes of soy foods or of soy isoflavones in Asian epidemiology [140].

Pharmaceutical inhibitors of CK2 are being pursued an anti-cancer drug candidates, as CK2 activity is elevated in many cancers and works in numerous complementary ways – including β-catenin up-regulation - to enhance cellular proliferation and survival [141-143]. However, it is notable that, in sub-micromolar concentrations, certain flavones and flavonols - including apigenin, luteolin, kaempferol, fisetin, quercetin, and myricetin - can inhibit CK2 [144-147]. This may rationalize numerous studies demonstrating that these flavonoids can retard cancer growth in mouse xenograft models [147]. The pharmaceutical utility of many flavonoids is limited by poor solubility that compromises absorption, as well as rapid conjugation after absorption, so fairly ample intakes may be needed for useful activity. Quercetin has the advantage of ample availability, and certain commercially available soluble derivatives such as isoquercitrin and enzymatically-altered isoquercitrin (employed as an antioxidant food additive in Japan) are capable of enabling far more efficient quercetin absorption [148-151]. A quercetin-enriched diet decreases polyp multiplicity in APC(Min/+) mice, and, in vitro, quercetin or isoquercitrin inhibit the growth and β-catenin activity of colorectal cancer cells [152-156]. Hence, quercetin or its more absorbable derivatives may have practical potential for prevention of colorectal cancer.

High Doses of Folate and Biotin May Boost Protective cGMP in Colon Epithelium

In regard to the tumor suppressor activity of cGMP, colon epithelium is known to express soluble guanylate cyclase activity that can respond to nitric oxide generated by nitric oxide synthase (NOS) activity within these cells or within enteric neurons [157]. Intriguingly, the NOS activity in colorectal cancers has been found to be uncoupled, as indicated by a high ratio of dihydro- to tetrahydrobiopterin [158]. If this effect is present in preneoplastic colon epithelium – likely as a consequence of oxidative stress - then measures which re-couple NOS might be expected to oppose colorectal cancer induction via cGMP. In vascular endothelium, high-dose folic acid has been shown to achieve a re-coupling of eNOS via induction of dihydrofolate reductase, which can reduce dihyrofolate to the active cofactor tetrahydrofolate [159,160]. If high-dose folate has a comparable effect in colorectal epithelium, it might be expected to oppose tumor promotion. In this regard, a controlled clinical trial in which 5 mg folate or placebo was administered daily for 3 years to patients with a past history of colorectal adenomas found that this comparatively high dose of folate reduced risk for recurrent adenomas by about two-thirds [161]. Analogous studies employing lower, more physiological doses of folic acid did not show such definitive benefit.

A more direct way to boost cGMP in colonic epithelium would be to administer high-dose biotin (10 or more mg biotin daily, in divided doses); at this supra-physiological intake, biotin can directly activated soluble guanylate cyclase by 2-3-fold [162- 164]. Such a regimen tends to be well tolerated in comparison to NO-releasing drugs, as NO can dose-dependently activate this enzyme by up to a hundred-fold, potentially precipitating severe hypotension. However, it should be noted that high-dose biotin supplementation can interfere with certain clinical assays that employ streptavidin-biotin technology [165]. To the best of our knowledge, high-dose biotin has never been tested in rodent models of intestinal tumor induction; such studies appear to be warranted.

Since phosphodiesterase 5 is expressed in colorectal epithelium, use of long-acting inhibitors of this enzyme such as tadalafil has evident potential for raising cGMP in colorectal epithelium, and thereby diminishing colorectal cancer risk [21].

Summing Up

Up-regulated β-catenin activity plays a key role in driving the induction of the large majority of colorectal cancers. This analysis suggests that lifestyle, pharmaceutical, and nutraceutical measures linked to lower risk for colorectal cancer decrease this risk, at least in part, by down-regulating β-catenin activity in colorectal epithelium. Such measures include ingestion of a whole-food fiber-rich plant-based diet, frequent consumption of cruciferous vegetables, aerobic exercise training, daily administration of lowdose aspirin, metformin treatment (and likely administration of the nutraceutical berberine), and increased ingestion of vitamin D, calcium, and soy isoflavones via diet or nutraceuticals. Furthermore, theoretical considerations suggest that high-dose supplementation with folate and biotin may have potential for suppressing β-catenin activity and decreasing colorectal cancer risk by boosting cGMP production in colorectal epithelium. Sesamol has interesting potential as an antioxidant for colorectal epithelium, and might aid colorectal cancer prevention if it became available as a nutraceutical. Quercetin, and its more soluble and absorbable derivatives isoquercitrin and enzymatically-modified isoquercitrin, may aid colorectal cancer prevention via CK2 inhibition. Astaxanthin may aid this prevention by boosting adiponectin levels. Development of innovative functional foods or nutraceuticals may make complex chemoprevention strategies for colorectal cancer more practical.

Figure 1:  Suppression of beta-catenin activity for prevention of colorectal CA.

Protective factors are high-lighted in bold.


  1. Wong NA, Pignatelli M (2002) Beta-catenin--a linchpin in colorectal carcinogenesis?. Am J Pathol 160: 389-401.
  2. Bian J, Dannappel M, Wan C, Firestein R (2020) Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer. Cells 9.
  3. Barker N, Morin PJ, Clevers H (2000) The Yin-Yang of TCF/beta-catenin signaling. Adv Cancer Res 77: 1-24.
  4. Lu FI, Sun YH, Wei CY, Thisse C, Thisse B (2014) Tissue-specific derepression of TCF/LEF controls the activity of the Wnt/β-catenin pathway. Nat Commun 5: 5368.
  5. Kim PJ, Plescia J, Clevers H, Fearon ER, Altieri DC (2003) Survivin and molecular pathogenesis of colorectal cancer. Lancet 362: 205-9.
  6. Lilien J, Balsamo J (2005) The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin. Curr Opin Cell Biol 17: 459-65.
  7. Brembeck FH, Rosário M, Birchmeier W (2006) Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev 16: 51-9.
  8. Gammons M, Bienz M (2018) Multiprotein complexes governing Wnt signal transduction. Curr Opin Cell Biol 51: 42-9.
  9. Zhang L, Shay JW (2017) Multiple Roles of APC and its Therapeutic Implications in Colorectal Cancer. J Natl Cancer Inst 109.
  10. Wang L, Zhang Q (2015) Application of the Apc(Min/+) mouse model for studying inflammation-associated intestinal tumor. Biomed Pharmacother 71: 216-21.
  11. Chen EY, Mazure NM, Cooper JA, Giaccia AJ (2001) Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation. Cancer Res 61: 2429-33.
  12. Fang D, Hawke D, Zheng Y et al. (2007) Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem 282: 11221-9.
  13. Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO (2006) Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem 281: 9971-6.
  14. Roura S, Miravet S, Piedra J, García de HA, DuÃach M (1999) Regulation of E-cadherin/Catenin association by tyrosine phosphorylation. J Biol Chem 274: 36734-40.
  15. Zeng G, Apte U, Micsenyi A, Bell A, Monga SP (2006) Tyrosine residues 654 and 670 in beta-catenin are crucial in regulation of Met-beta-catenin interactions. Exp Cell Res 312: 3620-30.
  16. Whitehead J, Vignjevic D, FÃtterer C, Beaurepaire E, Robine S, et al. (2008) Mechanical factors activate beta-catenin-dependent oncogene expression in APC mouse colon. HFSP J 2: 286-94.
  17. Li N, Xi Y, Tinsley HN et al. (2013) Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling. Mol Cancer Ther 12: 1848-59.
  18. Li N, Lee K, Xi Y et al. (2015) Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity. Oncogene 34: 1499-509.
  19. Browning DD, Kwon IK, Wang R (2010) cGMP-dependent protein kinases as potential targets for colon cancer prevention and treatment. Future Med Chem 2: 65-80.
  20. Lee K, Lindsey AS, Li N et al. (2016) β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget 7: 5353-65.
  21. Li N, Chen X, Zhu B et al. (2015) Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10. Oncotarget 6: 27403-15.
  22. Kwon IK, Wang R, Thangaraju M et al. (2010) PKG inhibits TCF signaling in colon cancer cells by blocking beta-catenin expression and activating FOXO4. Oncogene 2010 June 10;29(23):3423-34.
  23. Yarla NS, Gali H, Pathuri G et al. (2019) Targeting the paracrine hormone-dependent guanylate cyclase/cGMP/phosphodiesterases signaling pathway for colorectal cancer prevention. Semin Cancer Biol 56: 168-174.
  24. Topi G, Satapathy SR, Dash P et al. (2020) Tumour-suppressive effect of oestrogen receptor β in colorectal cancer patients, colon cancer cells, and a zebrafish model. J Pathol 251: 297-309.
  25. Amable G, Martínez-LeÃn E, Picco ME et al. (2019) Metformin inhibits β-catenin phosphorylation on Ser-552 through an AMPK/PI3K/Akt pathway in colorectal cancer cells. Int J Biochem Cell Biol 112: 88-94.
  26. Park SY, Kim D, Kee SH (2019) Metformin-activated AMPK regulates β-catenin to reduce cell proliferation in colon carcinoma RKO cells. Oncol Lett 17: 2695-2702.
  27. Seldin DC, Landesman-Bollag E, Farago M, Currier N, Lou D, et al. (2005) CK2 as a positive regulator of Wnt signalling and tumourigenesis. Mol Cell Biochem 274: 63-7.
  28. Zou J, Luo H, Zeng Q, Dong Z, Wu D, Liu L (2011) Protein kinase CK2α is overexpressed in colorectal cancer and modulates cell proliferation and invasion via regulating EMT-related genes. J Transl Med 9: 97.
  29. Lee AK, Ahn SG, Yoon JH, Kim SA (2011) Sox4 stimulates ß-catenin activity through induction of CK2. Oncol Rep 25: 559-65.
  30. Dowling JE, Alimzhanov M, Bao L et al. (2016) Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo. ACS Med Chem Lett 7: 300-5.
  31. Ponce DP, Maturana JL, Cabello P et al. (2011) Phosphorylation of AKT/PKB by CK2 is necessary for the AKT-dependent up-regulation of β-catenin transcriptional activity. J Cell Physiol 226: 1953-9.
  32. Ponce DP, Yefi R, Cabello P et al. (2011) CK2 functionally interacts with AKT/PKB to promote the β-catenin-dependent expression of survivin and enhance cell survival. Mol Cell Biochem 356: 127-32.
  33. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, et al. (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107: 1183-8.
  34. Jensen TSR, Mahmood B, Damm MB et al. (2018) Combined activity of COX-1 and COX-2 is increased in non-neoplastic colonic mucosa from colorectal neoplasia patients. BMC Gastroenterol 18: 31.
  35. Regan JW (2003) EP2 and EP4 prostanoid receptor signaling. Life Sci 74: 143-53.
  36. Araki Y, Okamura S, Hussain SP et al. (2003) Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways. Cancer Res 63: 728-34.
  37. Drew DA, Cao Y, Chan AT (2016) Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat Rev Cancer 16: 173-86.
  38. TomiÄ T, Domínguez-LÃpez S, Barrios-Rodríguez R (2019) Non-aspirin non-steroidal anti-inflammatory drugs in prevention of colorectal cancer in people aged 40 or older: A systematic review and meta-analysis. Cancer Epidemiol 58: 52-62.
  39. Flossmann E, Rothwell PM (2007) Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 369: 1603-13.
  40. Matusiak D, Murillo G, Carroll RE, Mehta RG, Benya RV (2005) Expression of vitamin D receptor and 25-hydroxyvitamin D3-1{alpha}-hydroxylase in normal and malignant human colon. Cancer Epidemiol Biomarkers Prev 14: 2370-6.
  41. Moreno J, Krishnan AV, Peehl DM, Feldman D (2006) Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway. Anticancer Res 26: 2525-30.
  42. Thill M, Fischer D, Hoellen F et al. (2010) Prostaglandin metabolising enzymes and PGE2 are inversely correlated with vitamin D receptor and 25(OH)2D3 in breast cancer. Anticancer Res 30: 1673-9.
  43. Zhang Y, Leung DY, Richers BN et al. (2012) Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 188: 2127-35.
  44. Chen TH, Kao YC, Chen BC, Chen CH, Chan P, et al. (2006) Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells. Eur J Pharmacol 541: 138-46.
  45. Ryu M, Kim EH, Chun M et al. (2008) Astragali Radix elicits anti-inflammation via activation of MKP-1, concomitant with attenuation of p38 and Erk. J Ethnopharmacol 115: 184-93.
  46. Turpeinen T, Nieminen R, Moilanen E, Korhonen R (2010) Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. J Pharmacol Exp Ther 333: 310-8.
  47. Gibbs DC, Fedirko V, Baron JA, et al. (2020) Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Colorectal Adenoma Patients in a Clinical Trial. Cancer Prev Res (Phila).
  48. Garland CF, Gorham ED (2017) Dose-response of serum 25-hydroxyvitamin D in association with risk of colorectal cancer: A meta-analysis. J Steroid Biochem Mol Biol 168: 1-8.
  49. McCarty MF (2012) Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention. Med Hypotheses 78: 45-57.
  50. Brewer AC, Sparks EC, Shah AM (2006) Transcriptional regulation of the NADPH oxidase isoform, Nox1, in colon epithelial cells: role of GATA-binding factor(s). Free Radic Biol Med 40: 260-74.
  51. Laurent E, McCoy JW, III, Macina RA et al. (2008) Nox1 is over-expressed in human colon cancers and correlates with activating mutations in K-Ras. Int J Cancer 123: 100-7.
  52. Shimizu S, Ishigamori R, Fujii G et al. (2015) Involvement of NADPH oxidases in suppression of cyclooxygenase-2 promoter-dependent transcriptional activities by sesamol. J Clin Biochem Nutr 56: 118-22.
  53. Lanone S, Bloc S, Foresti R et al. (2005) Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats. FASEB J 19: 1890-2.
  54. Jiang F, Roberts SJ, Datla S, Dusting GJ (2006) NO modulates NADPH oxidase function via heme oxygenase-1 in human endothelial cells. Hypertension 48: 950-7.
  55. Datla SR, Dusting GJ, Mori TA, Taylor CJ, Croft KD, et al. (2007) Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress. Hypertension 50: 636-42.
  56. McCarty MF (2007) Clinical potential of Spirulina as a source of phycocyanobilin. J Med Food 10: 566-70.
  57. Zheng J, Inoguchi T, Sasaki S et al. (2013) Phycocyanin and phycocyanobilin from Spirulina platensis protect against diabetic nephropathy by inhibiting oxidative stress. Am J Physiol Regul Integr Comp Physiol 304: R110-R120.
  58. Rodriguez AI, Gangopadhyay A, Kelley EE, Pagano PJ, Zuckerbraun BS, et al. (2010) HO-1 and CO decrease platelet-derived growth factor-induced vascular smooth muscle cell migration via inhibition of Nox1. Arterioscler Thromb Vasc Biol 30: 98-104.
  59. Saini MK, Vaiphei K, Sanyal SN (2012) Chemoprevention of DMH-induced rat colon carcinoma initiation by combination administration of piroxicam and C-phycocyanin. Mol Cell Biochem 361: 217-28.
  60. Saini MK, Sanyal SN (2014) Piroxicam and c-phycocyanin prevent colon carcinogenesis by inhibition of membrane fluidity and canonical Wnt/β-catenin signaling while up-regulating ligand dependent transcription factor PPARγ. Biomed Pharmacother 68: 537-50.
  61. Zhu Y, Yang Q, Liu H, Song Z, Chen W (2020) Phytochemical compounds targeting on Nrf2 for chemoprevention in colorectal cancer. Eur J Pharmacol 887: 173588.
  62. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, et al. (1999) Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274: 26071-8.
  63. Cheung KL, Lee JH, Khor TO et al. (2014) Nrf2 knockout enhances intestinal tumorigenesis in Apc(min/+) mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation. Mol Carcinog 53: 77-84.
  64. Cheung KL, Khor TO, Huang MT, Kong AN (2010) Differential in vivo mechanism of chemoprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM. Carcinogenesis 31: 880-5.
  65. Takahashi M, Fujii G, Hamoya T et al. (2019) Activation of NF-E2 p45-related factor-2 transcription and inhibition of intestinal tumor development by AHCC, a standardized extract of cultured Lentinula edodes mycelia. J Clin Biochem Nutr 65: 203-8.
  66. Wu QJ, Yang Y, Vogtmann E et al. (2013) Cruciferous vegetables intake and the risk of colorectal cancer: a meta-analysis of observational studies. Ann Oncol 24: 1079-87.
  67. Suh JH, Shenvi SV, Dixon BM et al. (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A 101: 3381-6.
  68. Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM (2009) Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta 1790: 1149-60.
  69. Lii CK, Liu KL, Cheng YP, Lin AH, Chen HW, et al. (2010) Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation. J Nutr 140: 885-92.
  70. Kochi T, Shimizu M, Sumi T et al. (2014) Inhibitory effects of astaxanthin on azoxymethane-induced colonic preneoplastic lesions in C57/BL/KsJ-db/db mice. BMC Gastroenterol 14: 212.
  71. Yasui Y, Hosokawa M, Mikami N, Miyashita K, Tanaka T (2011) Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem Biol Interact 193: 79-87.
  72. Prabhu PN, Ashokkumar P, Sudhandiran G (2009) Antioxidative and antiproliferative effects of astaxanthin during the initiation stages of 1,2-dimethyl hydrazine-induced experimental colon carcinogenesis. Fundam Clin Pharmacol 23: 225-34.
  73. Tanaka T, Kawamori T, Ohnishi M et al. (1995) Suppression of azoxymethane-induced rat colon carcinogenesis by dietary administration of naturally occurring xanthophylls astaxanthin and canthaxanthin during the postinitiation phase. Carcinogenesis 16: 2957-63.
  74. O'Keefe SJ, Li JV, Lahti L et al. (2015) Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun 6: 6342.
  75. Kim M, Park K (2018) Dietary Fat Intake and Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis of Prospective Studies. Nutrients 10.
  76. Ma Y, Hu M, Zhou L et al. (2018) Dietary fiber intake and risks of proximal and distal colon cancers: A meta-analysis. Medicine (Baltimore) 97: e11678.
  77. Gianfredi V, Salvatori T, Villarini M, Moretti M, Nucci D, et al. (2018) Is dietary fibre truly protective against colon cancer? A systematic review and meta-analysis. Int J Food Sci Nutr 69: 904-15.
  78. Topping DL (1996) Short-chain fatty acids produced by intestinal bacteria. Asia Pac J Clin Nutr 5: 15-9.
  79. Pan P, Oshima K, Huang YW et al. (2018) Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors. Int J Cancer 143: 886-96.
  80. Lee T, Schwandner R, Swaminath G et al. (2008) Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol Pharmacol 74: 1599-609.
  81. Zhou G, Myers R, Li Y et al. (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108: 1167-74.
  82. Musi N, Hirshman MF, Nygren J et al. (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51: 2074-81.
  83. Ng CW, Jiang AA, Toh EMS et al. (2020) Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression. Int J Colorectal Dis 35: 1501-12.
  84. Yang WT, Yang HJ, Zhou JG, Liu JL (2020) Relationship between metformin therapy and risk of colorectal cancer in patients with diabetes mellitus: a meta-analysis. Int J Colorectal Dis 35: 2117-31.
  85. Lee YS, Kim WS, Kim KH et al. (2006) Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55: 2256-64.
  86. Turner N, Li JY, Gosby A et al. (2008) Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes 57: 1414-8.
  87. Liang Y, Xu X, Yin M et al. (2019) Effects of berberine on blood glucose in patients with type 2 diabetes mellitus: a systematic literature review and a meta-analysis. Endocr J 66: 51-63.
  88. Piao M, Cao H, He N et al. (2016) Berberine Inhibits Intestinal Polyps Growth in Apc (min/+) Mice via Regulation of Macrophage Polarization. Evid Based Complement Alternat Med: 5137505.
  89. Chen YX, Gao QY, Zou TH et al. (2020) Berberine versus placebo for the prevention of recurrence of colorectal adenoma: a multicentre, double-blinded, randomised controlled study. Lancet Gastroenterol Hepatol 5: 267-75.
  90. Kim AY, Lee YS, Kim KH et al. (2010) Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol Endocrinol 24: 1441-52.
  91. Fujisawa T, Endo H, Tomimoto A et al. (2008) Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition. Gut 57: 1531-8.
  92. Mutoh M, Teraoka N, Takasu S et al. (2011) Loss of adiponectin promotes intestinal carcinogenesis in Min and wild-type mice. Gastroenterology 140.
  93. Dong Y, Zhou J, Zhu Y et al. (2017) Abdominal obesity and colorectal cancer risk: systematic review and meta-analysis of prospective studies. Biosci Rep: 37.
  94. Ryo M, Nakamura T, Kihara S et al. (2004) Adiponectin as a biomarker of the metabolic syndrome. Circ J 68: 975-81.
  95. Lu W, Huang Z, Li N, Liu H (2018) Low circulating total adiponectin, especially its non-high-molecular weight fraction, represents a promising risk factor for colorectal cancer: a meta-analysis. Onco Targets Ther 11: 2519-31.
  96. Lin Z, Tian H, Lam KS et al. (2013) Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 17: 779-89.
  97. Adams AC, Kharitonenkov A (2013) FGF21 drives a shift in adipokine tone to restore metabolic health. Aging (Albany NY) 5: 386-7.
  98. McCarty MF (2014) GCN2 and FGF21 are likely mediators of the protection from cancer, autoimmunity, obesity, and diabetes afforded by vegan diets. Med Hypotheses 83: 365-71.
  99. Laeger T, Henagan TM, Albarado DC et al. (2014) FGF21 is an endocrine signal of protein restriction. J Clin Invest 124: 3913-22.
  100. Castao-Martinez T, Schumacher F, Schumacher S et al. (2019) Methionine restriction prevents onset of type 2 diabetes in NZO mice. FASEB J 33: 7092-102.
  101. Yagi T, Toyoshima Y, Tokita R et al. (2019) Low-protein diet enhances adiponectin secretion in rats. Biosci Biotechnol Biochem 83: 1774-81.
  102. Yoshida H, Yanai H, Ito K et al. (2010) Administration of natural astaxanthin increases serum HDL-cholesterol and adiponectin in subjects with mild hyperlipidemia. Atherosclerosis 209: 520-3.
  103. Lundåsen T, Hunt MC, Nilsson LM et al. (2007) PPARalpha is a key regulator of hepatic FGF21. Biochem Biophys Res Commun 360: 437-40.
  104. Ong KL, Rye KA, O'Connell R et al. (2012) Long-term fenofibrate therapy increases fibroblast growth factor 21 and retinol-binding protein 4 in subjects with type 2 diabetes. J Clin Endocrinol Metab 97: 4701-8.
  105. Galman C, LundÃsen T, Kharitonenkov A et al. (2008) The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab 8: 169-74.
  106. Hussein G, Nakagawa T, Goto H et al. (2007) Astaxanthin ameliorates features of metabolic syndrome in SHR/NDmcr-cp. Life Sci 80: 522-9.
  107. Kishimoto Y, Yoshida H, Kondo K (2016) Potential Anti-Atherosclerotic Properties of Astaxanthin. Mar Drugs: 14.
  108. Mashhadi NS, Zakerkish M, Mohammadiasl J, Zarei M, Mohammadshahi M, et al. (2018) Astaxanthin improves glucose metabolism and reduces blood pressure in patients with type 2 diabetes mellitus. Asia Pac J Clin Nutr 27: 341-6.
  109. Allen NE, Appleby PN, Davey GK, Kaaks R, Rinaldi S, et al. (2002) The associations of diet with serum insulin-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans. Cancer Epidemiol Biomarkers Prev 11: 1441-8.
  110. Fontana L, Klein S, Holloszy JO (2006) Long-term low-protein, low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk. Am J Clin Nutr 84: 1456-62.
  111. Levine ME, Suarez JA, Brandhorst S et al. (2014) Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 19: 407-17.
  112. Chi F, Wu R, Zeng YC, Xing R, Liu Y (2013) Circulation insulin-like growth factor peptides and colorectal cancer risk: an updated systematic review and meta-analysis. Mol Biol Rep 40: 3583-90.
  113. Rinaldi S, Cleveland R, Norat T et al. (2010) Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies. Int J Cancer 126: 1702-15.
  114. Prior SJ, Jenkins NT, Brandauer J, Weiss EP, Hagberg JM (2012) Aerobic exercise training increases circulating insulin-like growth factor binding protein-1 concentration, but does not attenuate the reduction in circulating insulin-like growth factor binding protein-1 after a high-fat meal. Metabolism 61: 310-6.
  115. Wang J, Huang L, Gao Y et al. (2020) Physically active individuals have a 23% lower risk of any colorectal neoplasia and a 27% lower risk of advanced colorectal neoplasia than their non-active counterparts: systematic review and meta-analysis of observational studies. Br J Sports Med 54: 582-91.
  116. Cao H, Wang C, Chai R, Dong Q, Tu S (2017) Iron intake, serum iron indices and risk of colorectal adenomas: a meta-analysis of observational studies. Eur J Cancer Care (Engl ) 26.
  117. Qiao L, Feng Y (2013) Intakes of heme iron and zinc and colorectal cancer incidence: a meta-analysis of prospective studies. Cancer Causes Control 24: 1175-83.
  118. Bastide NM, Chenni F, Audebert M et al. (2015) A central role for heme iron in colon carcinogenesis associated with red meat intake. Cancer Res 75: 870-9.
  119. Burkitt DP (2017) Epidemiology of cancer of the colon and rectum. Cancer 28: 3-13.
  120. Cao H, Luo S, Xu M et al. (2014) The secondary bile acid, deoxycholate accelerates intestinal adenoma-adenocarcinoma sequence in Apc (min/+) mice through enhancing Wnt signaling. Fam Cancer 13: 563-71.
  121. Glinghammar B, Inoue H, Rafter JJ (2002) Deoxycholic acid causes DNA damage in colonic cells with subsequent induction of caspases, COX-2 promoter activity and the transcription factors NF-kB and AP-1. Carcinogenesis 23: 839-45.
  122. Powolny A, Xu J, Loo G (2001) Deoxycholate induces DNA damage and apoptosis in human colon epithelial cells expressing either mutant or wild-type p53. Int J Biochem Cell Biol 33: 193-203.
  123. Ocvirk S, O'Keefe SJ (2017) Influence of Bile Acids on Colorectal Cancer Risk: Potential Mechanisms Mediated by Diet - Gut Microbiota Interactions. Curr Nutr Rep 6: 315-22.
  124. Bayerdrffer E, Mannes GA, Richter WO et al. (1993) Increased serum deoxycholic acid levels in men with colorectal adenomas. Gastroenterology 104: 145-51.
  125. Bayerdrffer E, Mannes GA, OchsenkÃhn T, Dirschedl P, Wiebecke B, et al. (1995) Unconjugated secondary bile acids in the serum of patients with colorectal adenomas. Gut 36: 268-73.
  126. Pai R, Tarnawski AS, Tran T (2004) Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol Biol Cell 15: 2156-63.
  127. Farhana L, Nangia-Makker P, Arbit E et al. (2016) Bile acid: a potential inducer of colon cancer stem cells. Stem Cell Res Ther 7: 181.
  128. Khare S, Holgren C, Samarel AM (2006) Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2. Am J Physiol Gastrointest Liver Physiol 291: G1100-G1112.
  129. Centuori SM, Gomes CJ, Trujillo J et al. (2016) Deoxycholic acid mediates non-canonical EGFR-MAPK activation through the induction of calcium signaling in colon cancer cells. Biochim Biophys Acta 1861: 663-70.
  130. Keum N, Aune D, Greenwood DC, Ju W, Giovannucci EL (2014) Calcium intake and colorectal cancer risk: dose-response meta-analysis of prospective observational studies. Int J Cancer 135: 1940-8.
  131. Meng Y, Sun J, Yu J, Wang C, Su J (2019) Dietary Intakes of Calcium, Iron, Magnesium, and Potassium Elements and the Risk of Colorectal Cancer: a Meta-Analysis. Biol Trace Elem Res 189: 325-35.
  132. Huang D, Lei S, Wu Y et al. (2020) Additively protective effects of vitamin D and calcium against colorectal adenoma incidence, malignant transformation and progression: A systematic review and meta-analysis. Clin Nutr 39: 2525-38.
  133. Wargovich MJ, Eng VW, Newmark HL, Bruce WR (1983) Calcium ameliorates the toxic effect of deoxycholic acid on colonic epithelium. Carcinogenesis 4: 1205-7.
  134. Bartram HP, Kasper K, Dusel G et al. (1997) Effects of calcium and deoxycholic acid on human colonic cell proliferation in vitro. Ann Nutr Metab 41: 315-23.
  135. Chen GC, Pang Z, Liu QF (2012) Magnesium intake and risk of colorectal cancer: a meta-analysis of prospective studies. Eur J Clin Nutr 66: 1182-6.
  136. Wang A, Yoshimi N, Tanaka T, Mori H (1994) The inhibitory effect of magnesium hydroxide on the bile acid-induced cell proliferation of colon epithelium in rats with comparison to the action of calcium lactate. Carcinogenesis 15: 2661-3.
  137. DiNicolantonio JJ, McCarty MF, O'Keefe JH (2017) Decreased magnesium status may mediate the increased cardiovascular risk associated with calcium supplementation. Open Heart 4: e000617.
  138. McCarty MF (2006) Isoflavones made simple - genistein's agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses 66: 1093-114.
  139. Jackson RL, Greiwe JS, Schwen RJ (2011) Emerging evidence of the health benefits of S-equol, an estrogen receptor β agonist. Nutr Rev 69: 432-48.
  140. Yu Y, Jing X, Li H, Zhao X, Wang D (2016) Soy isoflavone consumption and colorectal cancer risk: a systematic review and meta-analysis. Sci Rep 6: 25939.
  141. Trembley JH, Chen Z, Unger G et al. (2010) Emergence of protein kinase CK2 as a key target in cancer therapy. Biofactors 36: 187-95.
  142. Cozza G (2017) The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design. Pharmaceuticals (Basel): 10.
  143. Lian H, Su M, Zhu Y, Zhou Y, Soomro SH, Fu H (2019) Protein Kinase CK2, a Potential Therapeutic Target in Carcinoma Management. Asian Pac J Cancer Prev 20: 23-32.
  144. Li C, Liu X, Lin X, Chen X (2009) Structure-activity relationship of 7 flavonoids on recombinant human protein kinase CK2 holoenzyme. Zhong Nan Da Xue Xue Bao Yi Xue Ban 34: 20-6.
  145. Lolli G, Cozza G, Mazzorana M et al. (2012) Inhibition of protein kinase CK2 by flavonoids and tyrphostins. A structural insight. Biochemistry 51: 6097-107.
  146. Russo M, Milito A, Spagnuolo C et al. (2017) CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia. Oncotarget 8: 42571-87.
  147. McCarty MF, Assanga SI, Lujan LL (2020) Flavones and flavonols may have clinical potential as CK2 inhibitors in cancer therapy. Med Hypotheses 141: 109723.
  148. Emura K, Yokomizo A, Toyoshi T, Moriwaki M (2007) Effect of enzymatically modified isoquercitrin in spontaneously hypertensive rats. J Nutr Sci Vitaminol (Tokyo) 53: 68-74.
  149. Motoyama K, Koyama H, Moriwaki M et al. (2009) Atheroprotective and plaque-stabilizing effects of enzymatically modified isoquercitrin in atherogenic apoE-deficient mice. Nutrition 25: 421-7.
  150. Makino T, Shimizu R, Kanemaru M, Suzuki Y, Moriwaki M, et al. (2009) Enzymatically modified isoquercitrin, alpha-oligoglucosyl quercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats. Biol Pharm Bull 32: 2034-40.
  151. Valentová K, Vrba J, Bancířová M, Ulrichová J, Křen V (2014) Isoquercitrin: pharmacology, toxicology, and metabolism. Food Chem Toxicol 68: 267-82.
  152. Shan BE, Wang MX, Li RQ (2009) Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Invest 27: 604-12.
  153. Park CH, Chang JY, Hahm ER, Park S, Kim HK, et al. (2005) Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Commun 328: 227-34.
  154. Murphy EA, Davis JM, McClellan JL, Carmichael MD (2011) Quercetin's effects on intestinal polyp multiplicity and macrophage number in the Apc(Min/+) mouse. Nutr Cancer 63: 421-6.
  155. Darband SG, Kaviani M, Yousefi B et al. (2018) Quercetin: A functional dietary flavonoid with potential chemo-preventive properties in colorectal cancer. J Cell Physiol 233: 6544-60.
  156. Amado NG, Predes D, Fonseca BF et al. (2014) Isoquercitrin suppresses colon cancer cell growth in vitro by targeting the Wnt/β-catenin signaling pathway. J Biol Chem 289: 35456-67.
  157. Pouokam E, Steidle J, Diener M (2011) Regulation of colonic ion transport by gasotransmitters. Biol Pharm Bull 34: 789-93.
  158. Rabender CS, Alam A, Sundaresan G et al. (2015) The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression. Mol Cancer Res 13: 1034-43.
  159. Siu KL, Miao XN, Cai H (2014) Recoupling of eNOS with folic acid prevents abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E null mice. PLoS One 9: e88899.
  160. Chalupsky K, Kraun D, Kanchev I, Bertram K, Grlach A (2015) Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase. Antioxid Redox Signal 23: 1076-91.
  161. Jaszewski R, Misra S, Tobi M et al. (2008) Folic acid supplementation inhibits recurrence of colorectal adenomas: a randomized chemoprevention trial. World J Gastroenterol 14: 4492-8.
  162. Vesely DL (1982) Biotin enhances guanylate cyclase activity. Science 216: 1329-30.
  163. Watanabe-Kamiyama M, Kamiyama S, Horiuchi K et al. (2008) Antihypertensive effect of biotin in stroke-prone spontaneously hypertensive rats. Br J Nutr 99: 756-63.
  164. McCarty MF, DiNicolantonio JJ (2017) Neuroprotective potential of high-dose biotin. Med Hypotheses 109: 145-9.
  165. Mock DM (2017) Biotin: From Nutrition to Therapeutics. J Nutr 147: 1487-92.

Copyright and Licensing: This is an Open Access Journal Article Published Under Attribution-Share Alike CC BY-SA: Creative Commons Attribution-Share Alike 4.0 International License. With this license readers can share, distribute, download, even commercially, as long as the original source is properly cited. Read More.


share article