CWP232228 targets liver cancer stem cells through Wnt/β-catenin signaling: a novel therapeutic approach for liver cancer treatment

Kim, Ji‐Young; Lee, Hwa‐Yong; Park, Kwan‐Kyu; Choi, Yang‐Kyu; Nam, Jeong‐Seok; Hong, In–Sun

doi:10.18632/oncotarget.7954

Cited by 69 publications

(53 citation statements)

References 58 publications

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“…CWP232228, PRI-724, and ipafricept are reported to decrease CSC marker expression, inhibit tumor spheroid formation, and decrease tumor metastasis. [45][46][47] b-Catenin-TCF4 complex formation is the ultimate and functional step in activating the canonical Wnt signaling to b-catenin pathway, and this interaction is considered an attractive target for cancer therapy. 48 In this study, we found that TRIB3 increases the association between b-catenin and TCF4 by tethering these proteins together.…”

Section: Discussionmentioning

confidence: 99%

TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis

Hua¹,

Shang²,

Yang³

et al. 2019

Gastroenterology

131

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Section: Discussionmentioning

confidence: 99%

TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis

Hua¹,

Shang²,

Yang³

et al. 2019

Gastroenterology

131

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“…We used this concentration in functional and molecular analyses to minimize the effect on cellular proliferation. Previously, we have discovered that Wnt/b-catenin signaling is activated to a greater extent in tumor cells than in normal cells and that it is further enhanced in CSC populations for regulating self-renewal activity and chemoresistance (29,33,34). Therefore, we hypothesized that niclosamide might target CSCs by inhibiting Wnt/b-catenin signaling.…”

Section: Niclosamide Inhibits Cancer Stemness and Therapy Resistance mentioning

confidence: 99%

Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness

Park

Kim

Choi

et al. 2019

Clinical Cancer Research

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Purpose: Niclosamide, an FDA-approved anthelmintic drug, has been characterized as a potent Wnt inhibitor that can suppress tumor growth and cancer stem-like cell (CSC) populations. However, the underlying molecular mechanisms remain poorly understood. This study aimed to examine how Wnt inhibition by niclosamide preferentially targets CSCs.Experimental Design: The mechanistic role of niclosamide in CSC inhibition was examined in public databases, human colorectal cancer cells, colorectal cancer xenografts, and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colorectal cancer model.Results: Niclosamide suppresses CSC populations and their self-renewal activities in colorectal cancer cells, and this CSCtargeting effect leads to irreversible disruption of tumorinitiating potential in vivo. Mechanistically, niclosamide downregulates multiple signaling components of the Wnt pathway, specifically lymphoid enhancer-binding factor 1 (LEF1) expression, which is critical for regulating stemness. Subsequently, we identified that the doublecortin-like kinase 1 (DCLK1)-B is a target of LEF1 and upregulates cancer stemness in colorectal cancer cells. We first documented that niclosamide blocks the transcription of DCLK1-B by interrupting the binding of LEF1 to DCLK1-B promoter. DCLK1-B depletion impairs cancer stemness resulting in reduced survival potential and increased apoptosis, thus sensitizing colorectal cancer to chemoradiation.Conclusions: Disruption of the LEF1/DCLK1-B axis by niclosamide eradicates cancer stemness and elicits therapeutic effects on colorectal cancer initiation, progression, and resistance. These findings provide a preclinical rationale to broaden the clinical evaluation of niclosamide for the treatment of colorectal cancer.

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“…166 The small-molecule inhibitor CWP232228 antagonizes the binding of β-catenin to TCF in the nucleus to induce apoptosis in liver CSCs. 167 In addition, temozolomide combined with miR-125b significantly induces apoptosis by targeting the Wnt/β-catenin signaling pathway in glioma stem cells. 168 Wnt/β-catenin signaling has been implicated in CSC-mediated metastasis.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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CWP232228 targets liver cancer stem cells through Wnt/β-catenin signaling: a novel therapeutic approach for liver cancer treatment

Cited by 69 publications

References 58 publications

TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis

TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis

Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness

Targeting cancer stem cell pathways for cancer therapy

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