Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/β-Catenin Pathway
Open accessAbstract
The Wnt/β-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/β-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/β-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced β-catenin accumulation, and inhibit Wnt/β-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/β-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC(50) values less than 1 µM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC(50) values are comparable to those shown to suppress the activities of Wnt/β-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/β-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.
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Niclosamide suppresses Wnt/β-catenin signaling by promoting Wnt co-receptor LRP6 degradation in cancer cells.
“In our previous studies, we have demonstrated that niclosamide (5-chloro-N-[2-chloro-4-nitrophenyl]−2-hydroxy benzamide), an FDA approved antihelminthic drug, suppresses Wnt/β-catenin signaling by promoting Wnt co-receptor LRP6 degradation in cancer cells [27, 37, 38].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [27]
Niclosamide induces Wnt co-receptor LRP6 degradation in cancer cells.
“On the other hand, niclosamide can induce Wnt co-receptor LRP6 degradation and suppress Wnt/β-catenin signaling in cancer cells [27, 37, 38], while CI-994 displays the opposite effect on LRP6 regulation by reducing LRP6 turnover.”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [27]
Niclosamide suppresses Wnt/β-catenin signaling in cancer cells.
“On the other hand, niclosamide can induce Wnt co-receptor LRP6 degradation and suppress Wnt/β-catenin signaling in cancer cells [27, 37, 38], while CI-994 displays the opposite effect on LRP6 regulation by reducing LRP6 turnover.”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [27]
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“Niclosamide targets the Wnt co-receptor LRP6 on the cell surface and that it is potent molecule as a Wnt/ β -catenin signaling and anti-cancer agent for human prostate and breast cancer due to in vitro studies (Lu et al., 2011).”
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“Cytosolic free b-catenin analysis was done with GST–Ecadherin binding assay (22).”
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“Again, niclosamide reduced levels of LRP6 and β-catenin.”
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WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer
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“It should also be pointed out that our pathway reporter analysis failed to demonstrate a significant inhibition of the Wnt signal pathway by niclosamide, which is in contrast to several prior reports [36, 37, 41, 46, 47, 53, 54].”
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“Niclosamide promoted LRP5/6 degradation [156], Wnt receptor Fzd1 endocytosis [157], downregulation of Dvl2 proteins, and inhibition of Wnt3A-stimulated β-catenin stabilization and TCF/LEF reporter activity [157,158] as well as enhanced cytotoxicity in all the patient derived tumor spheres.”
BackgroundA Role for the WNT Co-Receptor LRP6 in Pathogenesis and Therapy of Epithelial Cancers
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“Niclosamide-driven Dishevelled-2 and Frizzled 1 degradation may also rely on the induction of autophagosomes (36, 38).”
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“These results indicate that the LRP6 suppression was not at a transcriptional level but rather mediated by enhanced LRP6 degradation.(80) Niclosamide did not significantly affect the levels of cytosolic disheveled‐2 (Dvl2), another regulator of the Wnt/β‐catenin pathway.”
BackgroundInfluentialInhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness
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“Wnt/b-catenin inhibition by niclosamide has shown anticancer effects including tumor cell growth inhibition and tumor burden reduction in various types of cancer such as colorectal (20, 21), prostate (22), breast cancer (23), and glioblastoma (24).”
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“For example, niclosamide is an anthelminthic drug used for treating tapeworms in human, whereas accumulating studies also found that it can also target and inhibit the Wnt signaling in multiple types of cancer, such as ovarian cancer [128], colorectal cancer [129], prostate cancer and breast cancer [130], of note is t…”
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“Niclosamide lowers the levels of Dishevelled-2 (DVL2) and LRP6, components of the WNT pathway (40, 41).”
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“75 μM) [104], suggesting that WNT inhibition is involved in niclosamide’s anticancer effects.”
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Indole diterpene alkaloids as novel inhibitors of the Wnt/β-catenin pathway in breast cancer cells
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“Studies suggested that anti-proliferative and apoptosis inducing property of niclosamide is due to LRP6 degradation by inhibiting Wnt/b-catenin signalling [14].”
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The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche
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“Notably, niclosamide inhibited Wnt/β-catenin signaling by enhancing LRP6 degradation in TNBC cells and suppressed TNBC cell proliferation in vitro and tumor growth in vivo [25, 27].”
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Gigantol inhibits Wnt/β-catenin signaling and exhibits anticancer activity in breast cancer cells
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“Multiple small molecule LRP6 inhibitors, such as salinomycin [31], prodigiosin [23], niclosamide [32], silibinin [33] and rottlerin [34], have been identified to exert anticancer activity in breast cancer cells.”
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“It has been shown to inhibit the WNT/ β -catenin signaling pathway through inducing LRP6 degradation [59].”
BackgroundNiclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth
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“…of the pathway such as Tricostatin A (epigenetic regulator of DKK1 (Vibhakar et al., 2007)) hexachlorophene (ß-catenin inhibitor (Park et al., 2006)), and niclosamide (inducer of LRP6 degradation (Lu et al., 2011)) significantly decreased the appearance of lipid droplets in response to Wnt3a (Fig.”
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“Here, to exclude further that nuclear translocation of β-catenin is exclusively due to the positive feedback within the cell by Wnt3a, we used niclosamide, which is known to damage Wnt3a/β-catenin signaling activation by inducing LRP6 protein degradation [16].”
BackgroundNiclosamide enhances ROS-mediated cell death through c-Jun activation
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Wnt/β Catenin-Mediated Signaling Commonly Altered in Colorectal Cancer
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“More recently, IWP2, Wnt-C59, sFRP1, sFRP2, sFRP5, Wif1, and DKKs have been reported to inhibit tumors by interfering with the activation of Wnt signaling.(29-34)”
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“The free β-catenin then translocates from the cytoplasm to the nucleus, where it associates with T-cell factor (TCF)/lymphoid enhancing factor (LEF) to activate the expression of various downstream targeted genes that are responsible for regulating cell growth, proliferation, and apoptosis, thus mediating initiation a…”
BackgroundWinding back Wnt signalling: potential therapeutic targets for treating gastric cancers
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“number of mechanisms, through inducing LRP5/6 degradation [66], DVL2 down regulation [67, 68], FZD11 endocytosis and inhibits Wnt3a-stimulated β-catenin stabilization[68].”
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Targeting Wnt Signaling for Gastrointestinal Cancer Therapy: Present and Evolving Views
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“These notable activities of penitrem A are due, at least in part, to the inhibition of the Wnt/β-catenin pathway (Sallam et al. 2013a) that is a validated target of novel anticancer drugs (Lu et al. 2011).”
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Metabolic Strategies for Inhibiting Cancer Development
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“OXPHOS inhibition Niclosamide (105) Gamatrinib (106) Prostate cancer”
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Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation
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“2014), prostate (Lu et al. 2011), lung (Stewart et al.”
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“Several drugs such as salinomycin, prodigiosin, and niclosamide indeed induce LRP6 phosphorylation and degradation leading to decreased tumor growth (49, 50, 95).”
BackgroundNiclosamide suppresses macrophage-induced inflammation in endometriosis†
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Niclosamide inhibits ovarian carcinoma growth by interrupting cellular bioenergetics
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- Authors
- Lu, W., Lin, C., Roberts, M. J., Waud, W. R., Piazza, G. A., & Li, Y.
- Affiliations
- Southern Research Institute (US)
- University of South Alabama (US)
- Corresponding author
- Li, Yonghe
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-12-16
- Volume
- 6
- Issue
- 12
- Pages
- e29290
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3241710
- OpenAlex
- W2007145040
- Cited by
- 230
- References
- 50
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 16 · 2023: 10 · 2022: 12 · 2021: 18 · 2020: 22 · 2019: 19 · 2018: 17 · 2017: 20 · 2016: 21 · 2015: 21 · 2014: 14 · 2013: 8 · 2012: 5
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Rochester
- National Institutes of Health (RO1CA124531)
- National Cancer Institute (R01CA124531)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- niclosamide, LRP6, Wnt/β-catenin signaling, Wnt co-receptor, protein degradation, prostate cancer, breast cancer, apoptosis, anticancer drug repurposing, antihelminthic drugs, chemoprevention
- MeSH terms
- Dishevelled Proteins, Breast Neoplasms, Drug Screening Assays, Antitumor, Female, Humans, Male, Neoplasm Proteins, Neoplasms, Niclosamide, Phosphoproteins, Phosphorylation, Prostatic Neoplasms, Apoptosis, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Wnt Proteins, beta Catenin, HEK293 Cells, Proteolysis, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-6, Wnt3A Protein
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