Review Article - (2023) Volume 14, Issue 12

Regulating WNT Pathway by Natural Compounds

Shweta Kumari1*, Khushboo Raj2, Saurabh Kumar Gupta3 and Sudhanshu Mishra4
*Correspondence: Shweta Kumari, Department of Pharmacy, Gopal Narayan Singh University, Bihar, India, Email:

Author info »


This review currently focused on WNT, originates from wg, which means wingless and Ing denotes genes, having complicated network of ten homologous Frizzeled receptors (FzD), RYK (Receptor Like Tyrosine Kinase), Retinoic acid-related Orphan Receptors (RoR), Protein Tyrosine Kinase 7 (PTK7), Muscle Specific tyrosine Kinase (MuSK), co-receptors, Lipoprotein Receptor-related Protein (LRP5/6) and 19 cysteine rich glycolipoproteinswnt ligands. It is highly recommended pathways for the process of angiogenesis, embroyonic development by maintaining proliferation and differentiation. Most of the research is going in to know about cancer therapy or treatment by WNT pathways down regulation via canonical β-catenin dependent/ T-Cell Factor (TCF) pathway and non-ca-nonical β-catenin pathway. It is much needed way for developing the targeted therapies opposite to cancers, which involves phosphoryalation by Glycogen Synthase Kinase-3 (GSK-3) protein complex. In addition, there are some natural compounds which shows WNT pathway inhibitors. According to recent studies, Triple Negative Breast Cancer (TNBC) depends on WNT-pathway but no drugs are currently under clinical trials, it requires high cost in discovery and is a time consuming process. It clearly shows emergency for such type of drugs in cancer therapy.


WNT, Cancer, GSK-3 protein, Natural products, TNBC, Receptors


WNT is originated from the Wg(wingless) and Intgenes. Recessive mutations in the Wg genes affect wing development in Drosophila. Wnt is a family consists of 19 proteins and cysteine-rich glycoproteins. Wnt ligands activate several signaling pathways involved in the regulation of development at different stages (Zhang B and Ma JX, 2010).

Wnt pathway also plays an important role in angiogenesis. The Wnt pathway is one of the most important signaling cascades in the early events of embryonic development, where it controls cell proliferation and differentiation (Nusse R, 2005; Komiya Y and Habas R, 2008). Till date, the Wnt signaling is still not completely understood. This is mainly because it is it is a complicated network of ten G Protein Coupled Receptors (GPCR), homologue FZD receptors (Schulte G, 2015), Ryk, ROR, PTK, MuSK (Roy L and Dahl KDC, 2018), the co-receptors LRP5/6 (MacDonald BT and He X, 2012), and 19 glycolipoprotein Wnt ligands (Miller JR, 2001). There is a high degree of promiscuity in the ligand-receptor interactions, although certain Wnt have higher affinities to certain FZD receptors and co-receptors. To communicate, the cells engage with chemical signals, which, when received by the recipient cells, trigger defined intracellular signaling pathways in order to relay the information and provide the adequate response to the external stimuli. This enables the body to coordinate patterning and organ development during embryogenesis, to keep the organism in homeostasis and to respond to external stresses and inputs, and to regenerate after injury. On the cellular level, a signaling cascade is initiated by secreted ligands (e.g., hormones, cytokines, neurotransmitters, growth factors) produced by one cell, which then bind to a receptor on another cell. The receptors in most cases are located on the cell surface, and the signal is then relayed through intracellular components of the pathway, called transducers and second messengers, resulting in the corresponding cellular effect, for example target gene transcription or changes in an enzymatic activity (Uings IJ and Farrow SN, 2000; Shaw HV, et al., 2019). Aberrant Wnt signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Down regulation of the Wnt pathway is a desired mode of development of targeted therapies against these cancers. Wnt signaling is one of the essential pathways involved in animal embryonic development, during which it has numerous roles including the regulation of cell proliferation and differentiation In the healthy adult tissues however, it is largely inactive, with some exceptions such as the renewal of the gastro-intestinal tract as well as haematopoiesis and regeneration after injury It is to no surprise then that aberrant activation of this pathway can lead to diseases of neoplastic nature such as cancer (Nusse R, 2005; Krausova M and Korinek V, 2014; Malhotra S and Kincade PW, 2009; Whyte JL, et al., 2012; Polakis P, 2012).

The canonical Wnt signaling pathway is the most studied and well-characterized in various diseases including cancer, cardiovascular diseases and ocular diseases. Wnt operates either through canonical or non-canonical pathways which are differentiated by beta-catenin involvement (Shi J, et al., 2016). Wnt signaling is generally divided into three distinct branches-

• Canonical β-catenin dependent/TCF pathway

• Non-canonical β-catenin/TCF pathway/β-catenin independent

Literature Review

Canonical Wnt pathway

This is the common Wnt signaling pathway which is initiated by Wnt ligands. When the Wnt ligands are not present, then β-catenin a transcription factor, which act as a down-stream effector of this Wnt pathway, is begin to phosphorylate by a protein complex which contains GSK-3 in the cell cytosol and is keep on degrading to prevent its accumulation (Figure 1).


Figure 1: Canonical signaling Wnt pathway (Shi J, et al., 2016)

Non-canonical Wnt pathway

The non-canonical Wnt pathway is an unconventional pathway, comprises of several easily distinguishable branches and is also associated with some other activities which are independent of conventional Wnt/β-catenin signaling (Figure 2). The Wnt/PCP pathway regulates orientation of cellular structure. This pathway is further subdivided into two ways, which are


Figure 2: Non-canonical signaling pathway

• Planar Cell Polarity (PCP) pathway and

• Ca2+ pathway

Wnt inhibitory factor 1

Wnt Inhibitory factor 1 is Wnt pathway inhibitor, it get binds to Wnt ligands, similar. It was discovered back in 1999, where it was found to inhibit the somitogenesis in the development of Xenopus embryo, and it was also interacted with DrosophilaWingless and XenopusWnt (Uings IJ and Farrow SN, 2000). Although the WIF1 doesn’t found to share the CRD sequence neither with Fz or sFRPs, but however, it has a highly conserved WIF Domain (WD) which is an N-terminal domain, that contains 150 amino acids and it also contains a hydrophilic domain at C terminus with 45 amino acids, along with five Epidermal Growth Factor (EGF). The prostate, breast, lung and bladder cancers were directly correlated with the downregulated expression levels of WIF1(Figure 3).


Figure 3: Withanolide analogues in Wnt/β‐catenin signaling pathway

Wnt/β-catenin signaling: A therapeutic mechanism

Wnt/B-catenin signaling is activated by WNTs-a family of lipoglycoproteins, out of which 19 can be found in humans and by the fact the production, secretion and diffusion of them, through tissues is tightly controlled (Solis GP, et al., 2013). Just by binding to the FZD family of GPCRs (Koval A and Katanaev VL, 2011; Schulte G, 2015) (ten homologues in humans), and depending on the ligand-receptor combination and cellular context Wnt pathways can be activated. The most common of them is the PCP branch which is mostly involved in cytoskeleton rearrangement, cell polarity and migration; another one is Wnt/Ca2+ branch which promote proliferation and known to antagonize the canonical pathway; and then finally the so-called canonical branch (Komiya Y and Habas R, 2008) (Table 1).

Targeted gene Diseases
Tiam1 Colon tumors 
WNT5A  Leukemia 
MITF  Melanomas 
Tcf-1  Human colon cancer
LEF-1  Human colon cancer
Apc  CRC
Axin  Several cancers
MMP 2/9  T cells 
Endothelin 1 (END1) Human colon cancer 
AXIN2  Human cancer, tooth agenesis

Table 1: Target genes of the Wnt/β-catenin signaling pathway


Existing drugs and natural compounds: As Wnt pathway inhibitors

Natural Products (NPs) have been acting as a direct source of therapeutic agents and as a basis for drug development from many years as of now. Given are the natural compounds and drugs that are being used as inhibitors of Wnt pathway.

Vitamins: Retinoid which is used for cancer therapy (notably acute promyelocticleukemia) and chemoprevention, is synthesized from vitamin A from our body. Chemo preventive effects were seen in animal models with colorectal and breast cancers by an active form of vitamin D1α, 25-dihydroxyvitamin D3, and its synthetic derivatives. Earlier the mechanism of vitamins inhibiting Wnt/β-catenin pathway was unknown later it was suggested that activated nuclear receptors for vitamins interact with β-catenin and compete with TCFs also. It’s also found that both vitamin A and D might activate Wnt/β-catenin inhibitory proteins. E.g. Disabled 2 (Dab2) with the help of retinoic acid (Park CH, et al., 2005) (Table 2).

Inhibitors Subcategory Therapeutic medication
Small molecules Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Aspirin, Sulindac, Celecoxib
Existing drugs and natural compound
  • Vitamins
  • Polyphenols
Retinoids, 1 α 25,-dihydroxy-Vitamin D3
Querucetin, EGCG
Curcumin, Resveratrol, DIF

Table 2: Summary of inhibitors against Wnt signaling pathway

Polyphenols: Polyphenols are a group of chemicals found in plants, characterized by the presence of more than one phenol unit or building block per molecule. Several polyphenols, such as quercetin, Epigallocatechin3-Gallate (EGCG), curcumin, and resveratrol have been implicated as inhibitors of Wnt/β-catenin signaling pathway, although the mechanisms of action of these agents are not clear due to their inherent lack of specificity and inhibitory effects on multiple pathways (Kim J, et al., 2006; Rao CV, et al., 1995; Jaiswal AS, et al., 2002; Roccaro AM, et al., 2008; Morris HR, et al., 1987; Takahashi-Yanaga F, et al., 2003). The Differentiation-Inducing Factors (DIF) first identified in Dictyosteliumdiscoideum as putative morphogens required for stalk cell differentiation, also have a phenol unit and strongly inhibit the proliferation of human cancer cells. It has been reported that DIF-1 and DIF-3 inhibit the Wnt/β-catenin signaling pathway through the activation of GSK-3β (Yasmin T, et al., 2005; Mori J, et al., 2005; Takahashi-Yanaga F, et al., 2006). Apart from β-catenin, GSK- 3β has many target proteins such as glycogen synthase, Tau, CREB, and AP-1. Cyclin D1, a known oncogene, is also one of target molecules of GSK-3β, and phosphorylation by GSK-3β triggers cyclin D1 degradation (Sherr CJ, et al., 1996; Diehl JA, et al., 1998; Takahashi-Yanaga F, Sasaguri T, 2008). Because activators of GSK-3β, such as DIFs, could reduce cyclin D1 mRNA and protein levels, they may be applicable for the treatment of cancer and other proliferative disorders (Trosset JY, et al., 2006).

Curcumin: Natural derivatives of curcumin also inhibited the Wnt/β-catenin pathway, but it is through downregulation of p300, one of the transcriptional coactivators (Ryu MJ, et al., 2008). These studies suggest that the Wnt-antagonizing activity of curcumin can contribute to its anti-cancer and anti-angiogenesis effects (Conney AH, et al., 1991; Park CH, et al., 2005).

Querucetin: Quercetin inhibited the transcriptional activity of beta-catenin/Tcf in SW480 and also in HEK293 cells transiently transfected with constitutively active mutant beta-catenin gene, whose product is not induced to be degraded by APC-Axin-GSK3beta complex, so it was concluded that its inhibitory mechanism was related to beta-catenin itself or downstream components. Quercetin is an excellent inhibitor of beta-catenin/Tcf signaling in SW480 cell lines, and the reduced beta-catenin/Tcf transcriptional activity is due to the decreased nuclear beta-catenin and Tcf-4 proteins (Srivastava NS and Srivastava RA, 2019).

Epigallocatechin-3-gallate (EGCG): EGCG, which is the major polyphenolic constituent in green tea, attenuates Wnt pathway. EGCG on gastric cancer remain unclear. We found that EGCG significantly inhibited proliferation and increased apoptosis of SGC-7901 cells in vitroWnt/beta-catenin signaling in response to EGCG treatment of SW480 colon cancer cells, which show constitutively active Wnt pathway due to APC mutation. These cells were transfected with pTOPflash (beta-catenin/Tcf4 responsive reporter gene). 3h after transfection, cells were treated with increasing concentrations of EGCG. The pTOPflash luciferase activity was measured 24 h later and our results showed that Wnt/beta-catenin signaling was decreased in a dose dependent manner. Further pathway components through which EGCG inhibits the pathway, we transfected HEK293 cells, in which Wnt pathway is highly regulated, with mutant beta-catenin and pTOPflash (Yang C, et al., 2016; Ruonan Z and Wargovich M, 2007).

Resveratrol: Resveratrol, a dietary polyphenol, that has been shown to possess potent antioxidant as well as anti-inflammatory properties, mediates induction of antioxidant enzymes and modulates lipid metabolism while attenuating hepatic lipid peroxidation. The decreased nuclear localization of β-catenin by resveratrol treatment could be due to reduced expression of lgs and pygoI, which are regulators of β-catenin localization, showing significantly decrease the level of β-catenin in the nucleus of colon cancer cells (Frémont L, 2000; Hope C, et al., 2008).

Withanolides: Withanolide are the natural products extracted by using a pregnenolone-derived-lactone as the key intermediate that was transformed into a lactone appended to the D-ring of the steroidal scaffold. Only few clinical drug candidates that target Wnt signaling are available so far, and new small-molecule modulators of Wnt-related processes are in high demand. Dysregulation of Wnt signaling is linked to various diseases.

This natural product-inspired compound library contained potent inhibitors of Wnt signaling .Synthesis inspired by the natural product withanolide has yielded a potent inhibitor of the Wnt/β-catenin signaling pathway that acts by elevating Axin protein levels in a tankyrase-independent manner (Sheremet M, et al., 2017; Logan CY and Nusse R, 2004).

Jerusalem artichoke (Helianthus tuberosus): According to a study, the plant extract of Jerusalem was obtained using a special water extraction technology which is done under mild temperature conditions. This technology is one of its kind as it allows the extracting compound to be obtained in its natural state unlike the ethanol extraction method. The obtained extract was found to inhibit the Wnt pathway, and which was also reported to be confirmed by the beta-catenin stabilization assay, which is known to serve as an independent standard for the measurement of Wnt pathway activity (Logan CY and Nusse R, 2004).

Ampelopsis japonica: Extract of Ampelopsis japonica(a far Eastern plant) also found to inhibit Wnt pathway in both GFP and luciferase assays, as proved by some studies.

Jatrophone: Structurally Jatrophone is a macrocyclicditerpene. It has a unique oxaspiro core along with electrophilic centers. It was isolated from the Jatropha isabelliand Jatropha gossypiifolia,plants that belongs to the family Euphorbiacea. Along with its unique structure Jatrophone also displays many of biological properties, such as it is known to be anti-tumorous, cytotoxic, anti-inflammatory, anti-malarial and fungicidal. As soon we look into its Mechanism of Action (MOA), one can found that JA block the Wnt/β-catenin signaling somewhere between the receptor and β-catenin activation. It could also serve as a lead candidate molecule for development of anti-breast cancer agent for the management of disease in patients diagnosed with highly chemo-resistant metastatic TNBC (Logan CY and Nusse R, 2004; Fatima I, et al., 2017; Ling T, 2015).

Future Scope

According to the recent studies, along with various signaling pathways, Wnt inhibiting pathway is receiving great attention predominately, and the study of these pathways for their integral role in ocular diseases is or will be promising orientation in the field of research. As there are many known WNT-dependent cancers that exists, such as TNBC, with unmet medical needs which clearly indicates the future of drugs against these cancers, that they are in the first row to get the Food and Drug Administration (FDA) approval.


Wnt signaling is one of the developmental pathways, whose reactivation in many adult tissues underlies oncogenic transformation. As per the reports no drugs inhibiting the Wnt pathways are present in the current market and they are not even under process of any advanced clinical trials, so this clearly defines that the demand for such drugs is urgent. Targeting a selected pathway is hindered by several obstacles, with such complexed pathology in a multifactorial disease like cancer. As what have seen, the traditional drug discovery process has become a costly and time-consuming practice that is why massive improvement is still required upon developing a therapeutic intervention which is efficient enough for targeting Wnt signaling in tumors.


Author Info

Shweta Kumari1*, Khushboo Raj2, Saurabh Kumar Gupta3 and Sudhanshu Mishra4
1Department of Pharmacy, Gopal Narayan Singh University, Bihar, India
2Department of Pharmacy, Arka Jain University, Jamshedpur, India
3Department of Pharmacy, Rameshwaram Institute of Technology and Management Lucknow, Lucknow, India
4Department of Pharmaceutical Science, Rajiv Gandhi Proudyogiki Vishwavidyala, Bhopal, India

Citation: Kumari S: Regulating WNT Pathway by Natural Compounds

Received: 27-Nov-2023 Accepted: 11-Dec-2023 Published: 18-Dec-2023, DOI: 10.31858/0975-8453.14.12.747-752

Copyright: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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