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Pandey, P.; Khan, F.; Seifeldin, S.A.; Alshaghdali, K.; Siddiqui, S.; Abdelwadoud, M.E.; Vyas, M.; Saeed, M.; Mazumder, A.; Saeed, A. Flavonoids as Modulators of Dysregulated Wnt/β-Catenin Pathway. Encyclopedia. Available online: https://encyclopedia.pub/entry/48487 (accessed on 23 June 2024).
Pandey P, Khan F, Seifeldin SA, Alshaghdali K, Siddiqui S, Abdelwadoud ME, et al. Flavonoids as Modulators of Dysregulated Wnt/β-Catenin Pathway. Encyclopedia. Available at: https://encyclopedia.pub/entry/48487. Accessed June 23, 2024.
Pandey, Pratibha, Fahad Khan, Sara A. Seifeldin, Khalid Alshaghdali, Samra Siddiqui, Mohamed Elfatih Abdelwadoud, Manish Vyas, Mohd Saeed, Avijit Mazumder, Amir Saeed. "Flavonoids as Modulators of Dysregulated Wnt/β-Catenin Pathway" Encyclopedia, https://encyclopedia.pub/entry/48487 (accessed June 23, 2024).
Pandey, P., Khan, F., Seifeldin, S.A., Alshaghdali, K., Siddiqui, S., Abdelwadoud, M.E., Vyas, M., Saeed, M., Mazumder, A., & Saeed, A. (2023, August 25). Flavonoids as Modulators of Dysregulated Wnt/β-Catenin Pathway. In Encyclopedia. https://encyclopedia.pub/entry/48487
Pandey, Pratibha, et al. "Flavonoids as Modulators of Dysregulated Wnt/β-Catenin Pathway." Encyclopedia. Web. 25 August, 2023.
Flavonoids as Modulators of Dysregulated Wnt/β-Catenin Pathway
Edit

The Wnt pathway has been recognized for its crucial role in human development and homeostasis, but its dysregulation has also been linked to several disorders, including cancer. Wnt signaling is crucial for the development and metastasis of several kinds of cancer. Moreover, members of the Wnt pathway have been proven to be effective biomarkers and promising cancer therapeutic targets. Abnormal stimulation of the Wnt signaling pathway has been linked to the initiation and advancement of cancer in both clinical research and in vitro investigations. A reduction in cancer incidence rate and an improvement in survival may result from targeting the Wnt/β-catenin pathway.

flavonoids Wnt/β-catenin signaling natural product cancer

1. Introduction

Phytochemicals, particularly polyphenols, are among the most diverse and extensively researched classes of naturally occurring substances. This class includes subgroups of flavonoids and nonflavonoids. Flavonoids, also known as polyphenolic chemicals, are one of the most distinctive families of substances involved in plant metabolism and comprise an extensive group of natural compounds [1]. The subclasses, including flavones, chalcones, flavonols, and flavanones, are used to categorize almost 6000 of these compounds [2]. These substances eliminate the need to introduce foreign substances, which may cause individual complications. Because they are typically non-toxic, readily available, and more affordable than synthetic substances, they may result in the inhibition of various ailments in healthy individuals. Many studies have established the chemoprotective potential of flavonoids against various carcinomas [3]. It is generally known that a high consumption of fresh fruits and vegetables, particularly those rich in vitamins A, C, and E as well as beta-carotene, flavonoids, and other phytochemicals, protects against a variety of common malignancies in humans, including colon, breast, prostate, and lung cancers. Several substances have been proven to have antitumor properties in case–control investigations, cell culture experiments, and animal studies [4][5][6]. Recent research has shown that the ability of flavonoids to alter the Wnt/β-catenin signaling cascade is closely related to their antitumor properties [7][8]. Moreover, the ligand–receptor interaction (Wnt/Frizzled/LRP5/6) and methylation of targets encoding pathway elements, such as Wnt inhibitory factor 1 (WIF), have all been found to be affected by flavonoids [9][10]. Recent research reports have focused on the identification of numerous powerful compounds as potent inhibitors of the Wnt/β-catenin pathway, including EGCG (epigallocatechin-3-gallate), quercetin, genistein, kaempferol, baicalein, silibinin, naringenin, apigenin, fisetin, and luteoli.

2. Epigallocatechin-3-Gallate (EGCG)

Due to the existence of polyphenolic constituents in tea, several epidemiological research studies have demonstrated a potent reduction in the prevalence of carcinoma among those who regularly consume tea [11]. Green tea contains a lot of catechin, one of the most notable and well-known flavonoids. In a cup of brewed green tea, catechin EGC and epigallocatechin gallate (EGCG) make up between 30 and 40 percent of the dry weight (EGC). The most abundantly reported catechin in green tea is EGCG (epigallocatechin-3-monogallate). Although EGCG significantly inhibits the Wnt/β-catenin pathway, its mechanism still needs to be elaborated in detail. In a recent study, the Wnt signaling pathway was targeted, offering new information on how to prevent and treat gastric carcinoma. Reducing the expression levels of p-catenin (Ser552), β-catenin, p-GSK3 (S9), and EGCG blocked gastric cancer cell growth and showed that this suppressive action was correlated with canonical Wnt/β-catenin signaling [12].
Research on breast carcinoma has demonstrated that EGCG can block Wnt/β-catenin signaling without altering the expression levels of β-catenin by activating a transcriptional repressor called HBP-1. This has been demonstrated to be mediated by increased HBP1 mRNA stability [13][14]. Chen et al. further stated that EGCG treatment reduced the Wnt/β-catenin pathway activity, whereas LiCl-triggered activation of the pathway reversed the inhibitory potential of EGCG on spheroidal formation, cell growth, CSC markers, and death in colorectal cancer stem cells [15]. By inhibiting the Wnt/β-catenin pathway, EGCG also exerts an anticancer effect on lung CSCs in a similar manner [16].
It has been demonstrated that β-catenin protein (intracellular) stability is controlled by two APC-dependent mechanisms. The (APC/Axin/CK1/GSK-3β)-mediated pathway is the first pathway, followed by the (APC/Siah-1)-dependent pathway. Investigations further revealed a later mechanism that is not needed for EGCG-mediated β-catenin destruction [17]. According to Oh et al., treatment with EGCG did not downregulate mutant β-catenin at the Ser45 phosphorylation site of CK-1 or at the Ser37 phosphorylation site of GSK-3β. Phosphorylation of these special moieties is necessary for EGCG-induced β-catenin breakdown. Additionally, the authors found that the stability of β-catenin protein (intracellular) complex was unaffected by blocking GSK-3β activity or depleting it prior to EGCG treatment. They concluded that GSK-3 was not necessary for the EGCG-mediated degradation of β-catenin. Further research has established that EGCG can cause β-catenin degradation through a β-TrCp-mediated proteasomal mechanism, which in turn inhibits proliferation. EGCG seems to have greater efficacy than other catechins in preventing oxidative stress and tumorigenesis [17]. Studies have demonstrated that EGCG is a powerful Wnt inhibitor because it can reduce β-catenin levels and β-catenin/TCF-4 receptor activation in a dose-responsive manner [18]. Another effect of EGCG treatment on lung cancer H460 and A549 cell lines is a decrease in cytosolic β-catenin expression [19]. GSK3-α and GSK3-β activities has been demonstrated to be inhibited by EGCG treatment in HT29 colon cancer cells [20]. Additionally, it has been demonstrated that EGCG can block canonical Wnt signaling by downregulating the expression level of luciferase related to TCF/LEF [21]. In a study conducted by Singh et al., it was shown that EGCG can augment the amount of serine 33/37 residue in β-catenin via activating GK1/GSK-3. In skin cancer A431 and SCC13 cells, this promotes β-catenin breakdown and leads to an ensuing decrease in the nuclear aggregation of phosphorylated β-catenin [22]. It has been shown that EGCG administration reduces the expressions of DNMT1, Wnt, and β-catenin in the PC12 cell line, supporting the hypothesis that the Wnt/β-catenin signaling pathway is linked to cancer cell death [23]. The primary targets, GSK-3 and β-catenin, of the Wnt/β-catenin signaling pathway are downregulated by EGCG to produce its anticancer effects in human osteosarcoma cell lines MG63, 143B, and SaoS2 [24]. These results imply that EGCG may be a therapeutic candidate for the management of cancer by targeting abnormal Wnt/β-catenin signaling pathway.

3. Genistein

Genistein is a prominent isoflavone that is abundant in many plants, such as soybeans, tofu, and broccoli. Genistein, which has the chemical name [4′,5,7-trihydroxy isoflavonoid], can be found in food either in its free or esterified form. It has long been known that using soy products is associated with a lower chance of developing cancer. This is largely because soy products contain high genistein levels. This substance is found in Genista tinctoria L. plant and is soluble in different polar solvents. As previously mentioned, foodstuffs containing a soy base are the principal source of genistein [25]. Although genistein exhibits the desired bioavailability from a pharmacokinetic perspective, no proper safety assessment of genistein has yet been reported regarding its toxicokinetics. Studies have shown that isoflavones can significantly reduce β-catenin/Tcf-driven expression in AGS gastric carcinoma cells [26][27]. Moreover, Sarker et al. showed that isoflavones, particularly genistein, can increase GSK-3 expression, promote β-catenin binding to GSK-3, and increase β-catenin phosphorylation, which collectively inhibit the growth of prostate cancer [28]. Genistein can also attenuate Wnt-1-mediated cellular growth and its impact on c-Myc, VIZ, and cyclin D1 [29][30].
Studies have demonstrated that genistein inhibits Wnt signaling, which is linked to a decrease in pre-neoplastic lesions in the colon of male Sprague Dawley rats. Moreover, genistein administration suppresses the level of Wnt key elements, including Cyclin D1, c-Myc Wnt5a, Sfrp1, Sfrp2, and Sfrp5 [31][32]. Subsequent research has revealed that this phytochemical greatly reduces the level of β-catenin (CTNNBIP1) in colon cancer HT-29 cells [33].
Research using RT-PCR analysis has shown that genistein has anti-colorectal cancer properties mediated by the Wnt signaling pathway [34]. In SW1116 colon cancer cells, genistein lowered the level of WNT5a CpG island methylation, although DLD-1 and SW480 cells showed no such alteration. Additionally, genistein increased the expression of the sFRP2 gene by demethylating its silenced promoter in the colon cancer DLD-1 cell line, which inhibited β-catenin-mediated Wnt signaling [35]. In both in vitro and clinical RCC samples, miR-1260b was found to be highly expressed and dramatically reduced by genistein. Moreover, genistein decreased the expression of miR-1260b target genes, including sFRP1, Dkk2, and Smad4, thereby demonstrating a relationship with the Wnt signaling pathway [36]. By drastically reducing the mRNA levels of Wnt target genes, such c-myc and β-catenin in acute leukemia cells, genistein blocked the Wnt signaling pathway [37].

4. Quercetin

Quercetin, a plant flavonol derived from the polyphenol family, is a beneficial, readily available, and extremely potent natural chemical. It is abundant in fruits, vegetables, leaves, and other plants. Quercetin is employed to treat a wide range of ailments, such as malignancies, diabetes, and coronary heart diseases. Numerous studies have examined the antitumor effects of quercetin on cancer progression through signal transduction pathways, including PI3K/protein kinase B (AKT), Wnt/β-catenin, Janus kinase (JAK), signal transducer and transcription activator (STAT), NF-kB, and mitogen-activated protein kinase (MAPK) signaling cascades [38]. Numerous studies have shown that by targeting the Wnt/β-catenin pathway, the antitumor activity of quercetin has multidimensional effects. Mojsin et al. found that quercetin reduces β-catenin-dependent transcriptional efficacy in teratocarcinoma NT2/D1 cells by preventing SOX2, Nanog, and Oct4 mRNA levels, as well as inhibiting β-catenin nuclear movement [39]. Furthermore, Kim et al. demonstrated the antitumor efficacy of quercetin by inducing programmed cell death (apoptosis) in murine mammary carcinoma 4T1 cells. Recent research revealed that quercetin treatment resulted in enhanced expression of Wnt pathway regulators, including Dickkopf-related proteins (DKK) 1, 2, and 3, and concomitantly reduced cell viability [40]. Shan et al. examined Wnt signal transduction in human colon cancer SW480 cells, and they reported that quercetin reduced the level of cyclin D1 and survivin, two proteins that are associated with cell cycle regulation and death [41].
In a different study, Park et al. proposed that quercetin is a potent inhibitor of β-catenin/Tcf signaling in colon cancer SW480 cell lines and that decreased β-catenin/Tcf transcriptional ability is a result of reduced β-catenin (nuclear) and Tcf-4 proteins [42]. In a recent investigation using HT29 colon cancer cells, the effect of quercetin on a crucial regulator of the Wnt pathway, GSK3, was examined. Quercetin did not substantially prevent GSK3-α and GSK3-β at the selected doses; the total β-catenin expression in HT29 cells was almost unchanged. Thus, different biological and physiological conditions can result in various types of responses [20]. TGF-β is a key player in the metastasis and carcinogenesis of prostate carcinoma, and alterations in the elements of the Wnt signaling pathway are connected to different types of malignancies, including prostate cancer. In a study, quercetin demonstrated its anticancer effect in the prostate cancer PC-3 cell line through changes in EMT markers and Wnt signaling pathway components [43].

5. Baicalein and Baicalin

Baicalein (5,6,7-trihydroxyflavone) is a member of active flavonoids that is mostly present in the dried roots of the medicinal herb Scutellaria baicalensis. It has received a great deal of interest owing to its potential to inhibit cellular growth and apoptotic induction. Moreover, baicalein inhibits tumor growth by altering several cell signaling pathways, including p-Akt, p-mTOR, p-IB, and NF-kB [44]. In an osteosarcoma cell line, baicalein suppressed cell growth, boosted miR-25 expression, and controlled the Wnt/β-catenin pathway. Furthermore, baicalein and miR-25 enhanced GSK-3β expression and decreased Axin2 and β-catenin expressions. In addition, downregulation of miR-25 enhanced Axin2 and β-catenin expressions while decreasing GSK-3β expression [45]. Baicalein appeared to decrease overall β-catenin expression in osteosarcoma cells. It was observed that treatment with baicalein had no effect on the production of cytoplasmic β-catenin, which is transported from the cytoplasm to the nucleus and activates Wnt signaling. Moreover, baicalein treatment downregulated the expression levels of Wnt/β-catenin downstream effector genes, CD44, Oct3/4, and CCND (1,2), and survival. These findings imply that baicalein alters the translocation of the canonical Wnt/β-catenin pathway from the cytoplasm to the nucleus [46]. Osteocytes undergo carcinomatous transformation as a result of increased Wnt/β-catenin signaling, which aids in the growth of osteosarcomas. As determined by q-PCR and Western blotting, this mechanism is linked to lower expression of β-catenin and its crucial targets c-MYC. In line with this, subsequent research studies also revealed that baicalein targets several molecular markers through Wnt/β-catenin signaling to decrease osteosarcoma cell proliferation and promote cell death [47][48]. According to Xia et al., baicalein reduces the growth of cervical cancer cells by targeting the Wnt/β-catenin signaling pathway and CCND1. In cervical carcinoma HeLa, CaSki, C-33A, MS751, SN12C, and KBV1 cells, baicalein suppressed β-catenin nuclear movement and Wnt activity [49]. It has been demonstrated that baicalein can alter the mRNA and protein levels of β-catenin and its well-known downstream targets (cyclin D1, c-Myc, and Axin2) in T-lymphoblastic leukemia (T-ALL) [50]. Another study using breast cancer cells showed that baicalein exhibits antimetastatic properties by inhibiting SATB1 and the Wnt/β-catenin pathway. Baicalein significantly downregulates Wnt/β-catenin-targeted genes (Wnt1 and β-catenin) at the transcriptional and protein levels [51].
Furthermore, another important flavonoid of Scutellaria baicalensis, baicalin (7-D-Glucuronic acid-5,6-dihydroxyflavone), also demonstrates antitumor properties by targeting the Wnt/β-catenin signaling pathway in a few studies. In human osteosarcoma cell lines, baicalin has been demonstrated to activate apoptosis and autophagy by inhibiting the β-catenin signaling pathways [52]. Another study found that baicalin decreased the gene and protein expression levels of β-catenin in advanced-stage metastatic breast cancer cell lines. Upregulation of β-catenin by adenoviruses reversed these favorable impacts of baicalin on the migration and angiogenesis of breast cancer cells as well as their EMT [53].

6. Silibinin

Silibinin (flavonolignan) is a well-known natural dietary supplement extracted from milk thistle seed and has demonstrated biological activity against a range of malignancies via pleiotropic mechanisms [54]. Extensive molecular analysis indicated that silibinin targets signaling molecules responsible for the regulation of EMT, protease activation, migration, and invasion, as well as supporting tumor–microenvironment components, thereby preventing metastasis. Traditional uses of silibinin include dietary supplements for hepatoprotection; however, it has also been shown to have antitumor effects in a variety of in vitro and in vivo models of solid cancers, including carcinomas of the colon, skin, breast, lung, prostate, and kidney [55]. It has been established that its activity is related to regulation of the Wnt/β-catenin pathway. A human colorectal cancer cell line (SW480) and a xenograft model, where silibinin suppressed tumor progression by reducing the levels of β-catenin, c-Myc, and cyclin D1, also showed that the compound-induced reduction in cell growth was linked with the repression of the Wnt/β-catenin pathway [56]. In a different colon cancer animal study using A/J mice caused by AOM, silibinin administration had the same effect on tumor occurrence and multiplicity [57]. Comparable outcomes have also been observed in other in vivo models of colon tumorigenesis [58][59]. Additionally, in vitro experiments have demonstrated that silibinin prevents the motility and invasion of PC3 prostate cancer cells through a variety of mechanisms, including an increase in E-cadherin at the cell membrane and a decrease in nuclear β-catenin [60]. Another study showed that the Wnt co-receptor LRP6 is suppressed by silibinin and that its anticancer property is mediated by its influence on Wnt/LRP6 signaling in prostate and breast cancer cells [61]. An in vivo study using an ApcMin/transgenic mouse model of intestinal tumorigenesis further supported the anticancer efficacy of silibinin. This natural compound inhibits polyp growth in the small intestine and colon, and its anticarcinogenic efficacy is mediated by a reduction in β-catenin expression and transcriptional activity [62]. Additionally, Fan et al. showed that silibinin attenuates RCC metastasis and EMT in vitro and in vivo by modulating the Wnt/β-catenin signaling pathway. They also demonstrated that silibinin blocks the Wnt/β-catenin signaling cascade in an autophagy-mediated manner. The antimetastatic properties of silibinin against RCC are attributed to the autophagic destruction of β-catenin caused by silibinin [63].

7. Apigenin

Apigenin (4′,5,7,-trihydroxyflavone) is a natural flavonoid abundant in many fruits and vegetables.
The biological and pharmacological aspects of apigenin have been studied for many years. A growing body of studies have revealed that apigenin can modify the expression of important signaling pathways implicated in the carcinogenesis process, thereby inducing apoptosis [64]. Recent studies have shown that apigenin can reduce different kinds of malignancies, such as prostate, breast, lung, colorectal, liver, leukemia, ovarian, pancreatic, and cervical cancers. This is accomplished by inhibiting cancer cell metastasis, triggering apoptosis, and increasing immunity [65]. According to recent data, apigenin exposure has a directly impact on the Wnt/β-catenin expression [66]. The expression levels of downstream Wnt/β-catenin signaling effectors, including AXIN2, cyclin D1, and c-MYC, have also been shown to be modulated by apigenin [66]. Further research has revealed that apigenin significantly targets the crucial elements of Wnt/β-catenin signaling; however, its effects on LRP5 and Dishevelled (Dvl) are restricted [67]. In addition to inhibiting β-catenin movement to the nucleus through modulation of the PI3K/AkT/mTOR signaling pathway, apigenin decreases its accumulation and stability in the cytoplasm in a dose-responsive manner [67]. Moreover, apigenin overexpression inhibits the production of proto-oncogenes and suppresses the invasion and metastasis of colorectal cancer by suppressing Wnt/β-catenin signaling, while promoting the expression of E-cadherin and preventing the transportation of β-catenin to the nucleus [68]. These results suggest that apigenin may be a potential therapeutic alternative for the management of colorectal cancer.
According to Xu et al., apigenin reduced colorectal cancer cellular growth, migration, metastasis, and organoid development by impeding the Wnt/-catenin signaling pathway. Apigenin suppressed the stimulation of β-catenin/TCF/LEF signal by repressing the nuclear movement of β-catenin, which was increased by LiCl in a dose-responsive manner [69].
A long noncoding RNA, H19, which is typically increased in HCC, is known to play a critical role in promoting carcinogenesis and cancer development. Apigenin was found to downregulate H19 in a mouse model of xenograft tumors, which resulted in the attenuation of canonical Wnt/β-catenin signaling and tumor development [70]. Furthermore, Liu et al. demonstrated that apigenin reduced invasion and suppressed the proliferation of human OS cells by deactivating Wnt/β-catenin signaling. The repressive effect of apigenin on osteosarcoma cells was inversed by the upregulation of β-catenin, but it was strengthened by β-catenin downregulation [71]. In the dorsolateral prostate of TRAMP mice, apigenin treatment led to a higher expression of E-cadherin and lower expressions of β-catenin (nuclear), cyclin D1, and c-Myc. Similar outcomes were observed in TRAMP mice that already had tumors. Further similar results were observed when cancer cells were treated with β-catenin siRNA; apigenin exposure in DU145 prostate cancer cells increased E-cadherin protein expression, prevented nuclear movement of β-catenin and its accumulation in the cytoplasm, and declined c-Myc and cyclin D1 levels. These findings show that apigenin inhibits prostate tumorigenesis in TRAMP mice, at least in part, by preventing β-catenin signaling [72].

8. Luteolin

Luteolin (3′,4′,5,7-tetrahydroxyflavone) is a flavonoid that is present in different plants, medicinal herbs, fruits, and vegetables. It functions as an antitumor agent against different forms of human malignancies, such as glioblastoma, pancreatic, prostate, breast, and colon cancers. Moreover, it prevents the growth of cancer cells both in vitro and in vivo by preventing the proliferation of tumor cells, shielding them from carcinogenic stimuli, activating cell cycle arrest, and causing cell death via various signaling pathways [73]. In a 2013 study, it was found that luteolin administration in HCT-15 CRC cells had potent anti-proliferative effects by blocking Wnt/β-catenin signaling, triggering apoptotic cell death, and arresting the G2/M phase of cell growth [74]. It was also demonstrated that luteolin suppressed colon tumorigenesis induced by azoxymethane (AOM) by lowering the incidence and size of tumors. Luteolin inhibited cell proliferation by lowering the PCNA index and the number of argyrophilic nucleolar organizer region (AgNOR)/nuclei. This substance also prevents colon carcinogenesis by reducing AOM-induced cell proliferation through the participation of β-catenin, glycogen synthase kinase (GSK)-3, and cyclin D1, which are crucial elements in the Wnt signaling pathway [75]. According to Lin et al., luteolin also inhibited β-catenin mRNA and protein expression both in vitro and in vivo. They showed that luteolin significantly prevented breast cancer metastases by reversing EMT, which might be caused by β-catenin downregulation [76]. Han et al. revealed the efficacy of luteolin in prostate cancer PC-3 cells through the FZD6-mediated Wnt signaling pathway. It has also been shown that luteolin suppresses Wnt signaling irrespective of GSK-3β in prostate cancer cells by attenuating β-catenin transcriptional activity in GSK-3β-depleted cells [77].

9. Miscellaneous

Naringenin (4′,5,7-trihydroxyflavanone) is a prominent bioactive compound primarily found in citrus fruits, such grapefruits and other fruits, as well as in medicinal herbs. It belongs to the flavonoid class of polyphenols. As a herbal remedy, naringenin possesses significant pharmacological properties, including antioxidant, anti-inflammatory, neuroprotective, hepatoprotective, and anticancer activities, as per currently available reports. In vitro and in vivo investigations have demonstrated that carcinogens are rendered inactive after exposure to naringenin (pure), naringenin-loaded nanoparticles, or naringenin combined with chemotherapeutic drugs in a variety of malignancies. Naringenin suppresses the development of cancer through a variety of mechanisms, including pro-apoptosis, cell cycle arrest, inhibition of invasion, and modulation of several signaling pathways, including the Wnt/β-catenin, NF-kB, PI3K/Akt, and TGF-β pathways [78]. In gastric cancer cells, naringenin has also been shown by Lee et al. to suppress β-catenin/Tcf signaling through an unidentified mechanism [79]. Additional analysis revealed that 6-C-(E-phenylethenyl) naringenin (6-CEPN) has potent anti-liver cancer activity that is at least partially regulated by reducing the stemness of hepatocellular cells through a mechanism that involves Wnt/β-catenin signaling. It has been revealed that 6-CEPN inhibits nuclear translocation of β-catenin and causes its destruction by blocking Wnt/β-catenin signaling [80].
Fisetin (3,3′,4′,7-Tetrahydroxyflavone) has recently been identified as a Wnt/β-catenin signaling inhibitor [81]. Fisetin treatment of melanoma cells caused G1-phase arrest, reduced cell viability, and promoted disruption of Wnt/β-catenin signaling. The expression of Wnt protein and its co-receptors decreased along with this action, and endogenous Wnt inhibitor expression increased concurrently. Fisetin-treated cells displayed elevated cytosolic contents of Axin and β-TrCP and reduced GSK-3β phosphorylation in conjunction with reduced stability of β-catenin. Positively governed TCF targets, including c-myc, Mitf, and Brn-2, were downregulated as a consequence of fisetin-regulated interference with the enhanced cooperation among β-catenin and TCF-2 [81]. Interestingly, fisetin has been used to pharmacologically target Wnt/-catenin signaling dysregulation in colorectal cancer cells. When phosphorylated, β-catenin is ubiquitinated for destruction, whereas dephosphorylation causes stability and nuclear aggregation to transcriptionally modulate the transcription of target genes [82].

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