Regulation of Wnt receptor activity: Implications for therapeutic development in colon cancer

Zhong, Zhendong; Michalski, Megan N.; Stevens, Payton D.; Sall, Emily A.; Williams, Bart O.

doi:10.1016/j.jbc.2021.100782

Cited by 38 publications

(27 citation statements)

References 93 publications

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“…Additionally, simvastatin induced the receptor‐type tyrosine‐protein phosphatase PCP‐2 (PTPRU), which is known to be Nurr1 regulated, [ 36 ] the E3‐ubiquitin ligases RING finger protein RNF43 and RNF222, and notch4. RNF43 is considered as an anti‐apoptotic regulator, [ 37 ] as a Wnt antagonist [ 38 ] and to be involved in DNA repair [ 39 ] suggesting its upregulation as another neuroprotective contribution. Moreover, despite incomplete understanding of notch in neurodegeneration, [ 40 ] decreased notch signaling has been detected in AD [ 41 , 42 ] indicating a potential benefit of notch induction by simvastatin.…”

Section: Resultsmentioning

confidence: 99%

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

et al. 2022

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The ligand‐sensing transcription factor Nurr1 emerges as a promising therapeutic target for neurodegenerative pathologies but Nurr1 ligands for functional studies and therapeutic validation are lacking. Here pronounced Nurr1 modulation by statins for which clinically relevant neuroprotective effects are demonstrated, is reported. Several statins directly affect Nurr1 activity in cellular and cell‐free settings with low micromolar to sub‐micromolar potencies. Simvastatin as example exhibits anti‐inflammatory effects in astrocytes, which are abrogated by Nurr1 knockdown. Differential gene expression analysis in native and Nurr1‐silenced cells reveals strong proinflammatory effects of Nurr1 knockdown while simvastatin treatment induces several neuroprotective mechanisms via Nurr1 involving changes in inflammatory, metabolic and cell cycle gene expression. Further in vitro evaluation confirms reduced inflammatory response, improved glucose metabolism, and cell cycle inhibition of simvastatin‐treated neuronal cells. These findings suggest Nurr1 involvement in the well‐documented but mechanistically elusive neuroprotection by statins.

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Section: Resultsmentioning

confidence: 99%

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

et al. 2022

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“…Finally, we examined the signaling pathways in which these miRNAs could regulate. The top pathways upregulated by these miRNAs were the inflammatory IL-17 pathway and WNT pathway, both strongly correlated to tumorigenesis, evolution and progression of CC [ 22 , 23 ]. In contrast the most downregulated pathways were cGMP-PKG and Cholinergic synapse ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A microRNA panel that regulates proinflammatory cytokines as diagnostic and prognosis biomarkers in colon cancer

Martínez-Gutierrez

Carbajal-López

Bui

et al. 2022

Biochemistry and Biophysics Reports

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“…The APC/β-catenin pathway is upregulated in many CRCs and is an obvious pathway that could contribute to resistance to BRAF inhibitors [12]. This pathway has been suggested as a target in CRC but it has proven difficult due the lack of extracellular targets accessible to monoclonal antibodies and the lack of targets in the pathway with structures amenable to classical small drug development approaches [40,41]. However, a limited range of proof compounds are available that target this pathway and of those tested here the most effective was pyrvinium.…”

Section: Discussionmentioning

confidence: 99%

Response to BRAF-targeted Therapy Is Enhanced by Cotargeting VEGFRs or WNT/β-Catenin Signaling in BRAF-mutant Colorectal Cancer Models

Tran

Kolekar

Wang

et al. 2022

Molecular Cancer Therapeutics

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The fact that 10% of colorectal cancer (CRC) tumours harbor BRAF V600E mutations suggested targeting BRAF as a potential therapy. However, BRAF inhibitors have only limited single agent in this context. The potential for combination therapy has been shown by the BEACON trial where targeting the EGF receptor with cetuximab greatly increased efficacy of BRAF inhibitors in BRAF-mutant CRC. Therefore, we explored whether efficacy of the mutant BRAF inhibitor vemurafenib could be enhanced by co-targeting of either oncogenic WNT/β-catenin signalling or VEGFR signalling. We find the WNT/-catenin inhibitors pyrvinium, ICG-001 and PKF118-310 attenuate growth of CRC cell lines in vitro with BRAF-mutant lines being relatively more sensitive. Pyrvinium combined with vemurafenib additively or synergistically attenuated growth of CRC cell lines in vitro. The selective and potent VEGFR inhibitor axitinib was most effective against BRAF-mutant CRC cell lines in vitro but addition of vemurafenib did not significantly increase these effects. When tested in vivo in animal tumour models both pyrvinium and axitinib were able to significantly increase the ability of vemurafenib to attenuate tumour growth in xenografts of BRAF mutant CRC cells. The magnitude of these effects was comparable to that induced by a combination of vemurafenib and cetuximab. This was associated with additive effects on release from tumour cells and tumour microenvironment cell types of substances that would normally aid tumour progression. Taken together, this preclinical data indicates that the efficacy of BRAF inhibitor therapy in CRC could be increased by co-targeting either WNT/β-catenin or VEGFRs with small molecule inhibitors.

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Regulation of Wnt receptor activity: Implications for therapeutic development in colon cancer

Cited by 38 publications

References 93 publications

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

A microRNA panel that regulates proinflammatory cytokines as diagnostic and prognosis biomarkers in colon cancer

Response to BRAF-targeted Therapy Is Enhanced by Cotargeting VEGFRs or WNT/β-Catenin Signaling in BRAF-mutant Colorectal Cancer Models

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