Blocking the Wnt/β‑catenin signaling pathway to treat colorectal cancer: Strategies to improve current therapies (Review)

Chen, Yuxiang; Chen, Mo; Deng, Kai

doi:10.3892/ijo.2022.5472

Cited by 26 publications

(16 citation statements)

References 224 publications

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“…S3 ). As overexpression of TNKS can also activate the Wnt pathway 24 , we hypothesized that UAT-B might inhibit Wnt signaling activation induced by TNKS overexpression. Consistent with this hypothesis, we observed a marked decrease in TNKS protein levels when UAT-B and the protein synthesis inhibitor cycloheximide (CHX) were present ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

Zhu,

Gao,

Liu

et al. 2024

Acta Pharmaceutica Sinica B

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Section: Resultsmentioning

confidence: 99%

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

Zhu,

Gao,

Liu

et al. 2024

Acta Pharmaceutica Sinica B

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Section: Discussionmentioning

confidence: 99%

“…Wnt signalling regulates development and drives adult tissue stem cell maintenance. Although its malfunction is involved in cancer and many other diseases, it is therapeutically underexploited due to toxicity and limited efficacy [61,62]. Unfortunately, despite the potential of 1,25(OH)2D3 to interfere Wnt/β-catenin signalling, advanced CRCs often loss VDR expression and become unresponsive.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 mediates the antagonism of Wnt/β-catenin pathway by vitamin D in colon carcinoma cells

García-Martínez,

Chocarro-Calvo,

Martínez-Useros

et al. 2024

Preprint

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Cancer initiation and progression result from both genetic alterations and epigenetic reprograming caused by environmental or endogenous factors which can lead to aberrant cell signalling. Most colorectal cancers (CRC) are linked to the abnormal activation of the Wnt/ β-catenin pathway, whose key feature is the accumulation of acetylated β-catenin protein within the nucleus of colon epithelial cells. Nuclear β-catenin acts as a transcriptional co-activator that alters the expression of many target genes involved in cell proliferation and invasion. The most active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol) can antagonize the over-activated Wnt/ β-catenin pathway via binding to its high affinity receptor VDR. Here, we show that the activation of the SIRT1 deacetylase by 1,25(OH)2D3-bound VDR promotes deacetylation and nuclear exclusion of β-catenin and, consequently, the downregulation of its pro-tumorigenic target genes and the inhibition of human colon carcinoma cell proliferation. Notably, orthogonal SIRT1 activation systematically drives nuclear exclusion of β-catenin, highlighting the key role of SIRT1 in CRC. Since nuclear localization of β-catenin is a critical driver of CRC initiation and progression that requires its acetylation, our results provide a mechanistic basis for the epidemiological evidence linking vitamin D deficiency and increased CRC risk and mortality.

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“…Interestingly, the Wnt-signaling pathway, which ultimately activates MYC and Ne-MT genes, may be a potential therapeutic target. Currently several drugs targeting this pathway are being tested in clinical trials (44).…”

Section: Discussionmentioning

confidence: 99%

MAML3-fusions modulate Vascular and Immune Tumor Microenvironment and Confer High Metastatic Risk in Pheochromocytoma and Paraganglioma

Monteagudo,

Calsina,

Martínez-Montes

et al. 2023

Preprint

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Background Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that encompass a genetically heterogeneous disease. Approximately 20-25% of diagnosed cases develop metastases, for which there is an absence of predictive markers and therapeutic stratification strategies. MAML3-fusions in PPGL are associated with increased metastatic risk; however, neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed so far and its prevalence remains unclear. Methods We compiled a total of 779 patients, through the combination of publicly-available and novel data from 10 different series. Omic data, FISH and PD-L1 IHC, were used to identify MAML3-fusion positive PPGLs, which were validated by a custom NGS panel and PCR assays. Differential expression and gene set enrichment analyses were conducted to elucidate distinctive features of MAML3-tumors. CD31 IHC analysis was used to study vascular phenotype, and a classification system was generated according to criteria of homogeneity, number, length and branching of vessels. The immune infiltration of pro-tumor M2 macrophages was examined using lymphocytes infiltration. Results Fusion prevalence stood at 4% (34/779), being the largest MAML3 series reported so far. Patients with MAML3-fusion are mainly single noradrenergic pheochromocytomas, which tend to accumulate secondary events in ATRX. However, we also found two patients with multiple MAML3-related tumors, suggesting a post-zygotic fusion event. MAML3-tumors exhibit a significantly shorter time to metastasis compared to other genotypes, supported by an increased expression of neuroendocrine-to-mesenchymal transition genes and MYC targets. Moreover, these tumors display a unique vascular architecture linked to a characteristic extracellular matrix profile. These tumors present a distinctive immune profile, characterized by PD-L1 and CD40 overexpression, and infiltrating pro-tumor macrophages and NK/cytotoxic cells, making them different from other “immune-cold” metastatic PPGLs. Conclusions Our study highlights the relevance of MAML3-fusions in the context of metastatic PPGLs. We uncovered the presence MAML3-tumor-specific vulnerabilities, such as the Wnt-pathway dysregulation, the rich vascular network, making them susceptible to respond to Wnt-inhibitors and anti-angiogenic therapies. The immune cell infiltration profile suggests that targeting CD40 may be a therapeutic option for these patients, and the clear overexpression of PD-L1 offers an opportunity to reopen clinical trials with MAML3-fusion patients as the ideal candidates.

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Blocking the Wnt/β‑catenin signaling pathway to treat colorectal cancer: Strategies to improve current therapies (Review)

Cited by 26 publications

References 224 publications

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

SIRT1 mediates the antagonism of Wnt/β-catenin pathway by vitamin D in colon carcinoma cells

MAML3-fusions modulate Vascular and Immune Tumor Microenvironment and Confer High Metastatic Risk in Pheochromocytoma and Paraganglioma

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