The Role of WNT Pathway Mutations in Cancer Development and an Overview of Therapeutic Options

Groenewald, Wibke; Lund, Anders H.; Gay, David M.

doi:10.3390/cells12070990

Cited by 15 publications

(10 citation statements)

References 129 publications

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“…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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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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“…Mutations in key genes of the WNT pathway, such as CTNNB1 and AXIN1, have been observed in BWS embryonal tumors, including hepatoblastoma, Wilms tumor, and pancreatoblastoma [45]. In addition, alterations in the WNT pathway have been associated with growth defects, a hallmark feature of BWS [28].…”

Section: Wnt Pathway Analysis In Bws and Control Cell Linesmentioning

confidence: 99%

Dysfunction in IGF2R Pathway and Associated Perturbations in Autophagy and WNT Processes in Beckwith–Wiedemann Syndrome Cell Lines

Pileggi,

Colombo,

Ancona

et al. 2024

IJMS

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Beckwith–Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS’s characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development.

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“…Human colon cancers that lack APC mutations frequently have activating mutations in CTNNB1 (β-catenin) that prevent its phosphorylation by GSK-3, demonstrating a key epistatic relationship between APC and CTNNB1 /β-catenin [ 130 , 131 ]. Activating mutations in CTNNB1/ β-catenin (23–36%) and loss-of-function mutations in AXIN (5–10%) are common in hepatocellular cancer [ 132 , 133 ] and, along with other Wnt pathway mutations, are also observed in melanoma, uterine, gastric, and pancreatic ductal adenocarcinomas [ 133 , 134 , 135 , 136 ].…”

Section: Wnt Signalingmentioning

confidence: 99%

When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex

Li,

Furth,

Rustgi

et al. 2023

Cells

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The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a “canonical” Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers.

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The Role of WNT Pathway Mutations in Cancer Development and an Overview of Therapeutic Options

Cited by 15 publications

References 129 publications

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

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

Dysfunction in IGF2R Pathway and Associated Perturbations in Autophagy and WNT Processes in Beckwith–Wiedemann Syndrome Cell Lines

When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex

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