Therapeutic Potential of Targeting Wnt/β-Catenin Pathway in Treatment of Colorectal Cancer: Rational and Progress

Bahrami, Afsane; Amerizadeh, Forouzan; Shahidsales, Soodabeh; Khazaei, Majid; Ghayour‐Mobarhan, Majid; Sadeghnia, Hamid Reza; Maftouh, Mina; Hassanian, Seyed Mahdi; Avan, Amir

doi:10.1002/jcb.25903

Cited by 142 publications

(110 citation statements)

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“…A number of approaches have been tested to target this interaction, including the use of natural compounds (37), small molecule inhibitors (38) and antibody-based inhibitors (8), with promising results (37). Natural compounds, including curcumin, 3,3-diindolylmethane, and phytoestrogen, have been tested for their capacity to reduce the activity of WNT signaling in cancer cells.…”

Section: Wnt-related Potential Candidates For Overcoming Chemoresistancementioning

confidence: 99%

“…Natural compounds, including curcumin, 3,3-diindolylmethane, and phytoestrogen, have been tested for their capacity to reduce the activity of WNT signaling in cancer cells. Synthetic/small WNT inhibitors, including rofecoxib (cyclooxygenase-2 inhibitor), PRI-724 (β-catenin antagonist) and CWP232291 (synthetic/small WNT inhibitor), and the monoclonal antibody against Fzd receptors, vanituctumab, have been described (37). According to previous literature, several families of secreted antagonists consist of secreted frizzled-related proteins (sFRPs), the Dickkopf (Dkk) protein family, sclerostin (a soluble WNT antagonist), cerberus and WNT inhibitory factor-1 (39,40).…”

Section: Wnt-related Potential Candidates For Overcoming Chemoresistancementioning

confidence: 99%

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Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

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Abstract. Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

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Section: Wnt-related Potential Candidates For Overcoming Chemoresistancementioning

confidence: 99%

Section: Wnt-related Potential Candidates For Overcoming Chemoresistancementioning

confidence: 99%

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

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“…For example, epigenetic and genetic alterations of β-catenin and adenomatous polyposis coli (APC) regulators in the Wnt signaling pathway have been demonstrated in many human tumors, including liver cancer [6], gastric cancer [7, 8] and colon cancer [9, 10]. Therefore, aberrant activation of WNT signaling is a hallmark of carcinogenesis [11, 12], and epigenetic modifications are an important mechanism for regulating this pathway [13]. …”

Section: Introductionmentioning

confidence: 99%

Dickkopf-Related Protein 2 is Epigenetically Inactivated and Suppresses Colorectal Cancer Growth and Tumor Metastasis by Antagonizing Wnt/β-Catenin Signaling

Wang

Yue

Shao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Aberrant activation of the Wnt/β-catenin signaling pathway plays a key role in the pathogenesis of multiple tumors including digestive cancers. Recent studies have reported that Dickkopf-related protein 2 (DKK2) is epigenetically inactivated in numerous types of cancers and that its gene products exhibit tumor-suppressive properties. However, the biological functions and underlying molecular mechanisms of DKK2 in colon carcinoma remains obscure. Methods: We examined the expression of DKK2 in colon tumor cell lines by RT-PCR and its promoter methylation status in colon tumor cell lines and primary tumors by methylation-specific PCR (MSP). Ectopic expression of DKK2 was measured by RT-PCR prior to the other experiments. To investigate the function of DKK2, we assayed colony formation and cell proliferation, utilized flow cytometric analyses of the cell cycle and acridine orange/ethidium bromide (AO/EB) fluorescence staining for apoptosis, and examined wound healing, transwell migration and tumor growth in vivo. Western blots were used to explore the mechanisms of DKK2 in epithelial- mesenchymal transition and canonical Wnt/β-catenin signaling. Results: We show here that downregulation or silencing of DKK2 was closely associated with the hypermethylation status of its promoter and that DKK2 expression could be restored by demethylation treatment. Methylation of the DKK2 promoter was detected in nearly all tumors and tumor-adjacent tissues, but not in normal colon tissues. Ectopic expression of DKK2 in colon cell lines HCT116 and HT-29 inhibited colony formation and cell viability by inducing cell cycle G0/G1 arrest and apoptosis, and growth of stable DKK2-infected HCT116 cells in nude mice was decreased compared to controls. Furthermore, DKK2 restrained cell migration through partial reversal of epithelial-to- mesenchymal transition and also by downregulating several stem cell markers. Our data further showed that restoration of DKK2 expression resulted in downregulation of active β-catenin and its downstream target genes. Conclusion: DKK2 appears to be a functional tumor suppressor regulating tumorigenesis of colorectal cancer by antagonizing Wnt/β-catenin signaling.

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“…In an effort to overcome these barriers, there have been small molecule screens which have suggested other potential inhibitors of β-catenin pathway exist and can be effective. 42–44 For example, PRI-724 is an antagonist of canonical β-catenin transcription that inhibits the interaction between β-catenin and cAMP response element-binding protein (CREB)-binding protein (CBP). It has been shown to be tolerated in human phase I studies with planned phase II efficacy studies in combination with the anti-VEGF antibody bevacizumab planned for patients with metastatic colorectal carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown to be tolerated in human phase I studies with planned phase II efficacy studies in combination with the anti-VEGF antibody bevacizumab planned for patients with metastatic colorectal carcinoma. 42,44 Another small molecule inhibitor, CWP232291, which binds to Src-Associated substrate in Mitosis of 68 kDa (Sam68) has been found to inhibit canonical β-catenin transcription and is being tested in a phase I toxicity trial for patients with hematologic malignancies. 42,43 Whether such agents have a role in WT or other malignancies remains to be determined, but our studies offer a proof of principle that such investigations are warranted.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor

et al. 2017

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Wilms tumor (WT) is the most common renal malignancy of childhood and the fourth most common pediatric solid malignancy in the United States. While the mechanisms underlying the WT biology are complex, these tumors most often demonstrate activation of the canonical Wnt/β-catenin pathway. We and others have shown that constitutive activation of β-catenin restricted to the renal epithelium is sufficient to induce primitive renal epithelial tumors which resemble human WT. Here we demonstrate that pharmacologic inhibition of β-catenin gene transcription with pyrvinium inhibits tumor growth and metastatic progression in a murine model of WT. Cellular invasion is significantly inhibited in both murine WT-like and human WT cells and is accompanied by downregulation of the oncogenes Myc and Birc5 (survivin). Our studies provide a proof of concept that the canonical Wnt/β-catenin pathway may be a novel therapeutic target in the management of WT.

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Therapeutic Potential of Targeting Wnt/β-Catenin Pathway in Treatment of Colorectal Cancer: Rational and Progress

Cited by 142 publications

References 50 publications

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

Dickkopf-Related Protein 2 is Epigenetically Inactivated and Suppresses Colorectal Cancer Growth and Tumor Metastasis by Antagonizing Wnt/β-Catenin Signaling

Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor

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