The role of Wnt signaling pathway in carcinogenesis and implications for anticancer therapeutics

Sheikh, A; Niazi, Asfandyar Khan; Ahmed, Muhammad Zafar; Iqbal, Bushra; Anwer, Syed Muhammad Saad; Khan, Hira Hussain

doi:10.1186/1897-4287-12-13

Cited by 15 publications

(14 citation statements)

References 46 publications

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“…WNT ligands belong to the family of genes observed in humans, Xenopus, mice, drosophilia, and Zebrafish ( 31 ). Dysregulation of the canonical WNT pathway activity has been reported in several disorders and cancers ( 32 – 34 ).…”

Section: Canonical Wnt/β-catenin Pathwaymentioning

confidence: 99%

Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis

2018

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Inflammation and oxidative stress are common and co-substantial pathological processes accompanying, promoting, and even initiating numerous cancers. The canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARγ) generally work in opposition. If one of them is upregulated, the other one is downregulated and vice versa. WNT/β-catenin signaling is upregulated in inflammatory processes and oxidative stress and in many cancers, although there are some exceptions for cancers. The opposite is observed with PPARγ, which is generally downregulated during inflammation and oxidative stress and in many cancers. This helps to explain in part the opposite and unidirectional profile of the canonical WNT/β-catenin signaling and PPARγ in these three frequent and morbid processes that potentiate each other and create a vicious circle. Many intracellular pathways commonly involved downstream will help maintain and amplify inflammation, oxidative stress, and cancer. Thus, many WNT/β-catenin target genes such as c-Myc, cyclin D1, and HIF-1α are involved in the development of cancers. Nuclear factor-kappaB (NFκB) can activate many inflammatory factors such as TNF-α, TGF-β, interleukin-6 (IL-6), IL-8, MMP, vascular endothelial growth factor, COX2, Bcl2, and inducible nitric oxide synthase. These factors are often associated with cancerous processes and may even promote them. Reactive oxygen species (ROS), generated by cellular alterations, stimulate the production of inflammatory factors such as NFκB, signal transducer and activator transcription, activator protein-1, and HIF-α. NFκB inhibits glycogen synthase kinase-3β (GSK-3β) and therefore activates the canonical WNT pathway. ROS activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling in many cancers. PI3K/Akt also inhibits GSK-3β. Many gene mutations of the canonical WNT/β-catenin pathway giving rise to cancers have been reported (CTNNB1, AXIN, APC). Conversely, a significant reduction in the expression of PPARγ has been observed in many cancers. Moreover, PPARγ agonists promote cell cycle arrest, cell differentiation, and apoptosis and reduce inflammation, angiogenesis, oxidative stress, cell proliferation, invasion, and cell migration. All these complex and opposing interactions between the canonical WNT/β-catenin pathway and PPARγ appear to be fairly common in inflammation, oxidative stress, and cancers.

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Section: Canonical Wnt/β-catenin Pathwaymentioning

confidence: 99%

Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis

2018

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“…Finally, OMP-54F28, a fusion protein of the FZD8 ligand-binding domain that binds to all Wnt ligands, is now being tested in a phase I trial for treatment of solid tumors including PCa (NCT01608867) [72] .…”

Section: Wnt Signaling Pathwaymentioning

confidence: 99%

“…A number of therapeutic agents targeting the Wnt pathway are under investigation and monoclonal antibodies (mAb) against the Wnt cascade have been tested with promising anti-tumor activity [35,72] . A small molecule inhibitor, Wnt inhibitor 3289-8625, has also been shown to inhibit the growth of PC3 PCa cells in vitro [73] .…”

Section: Wnt Signaling Pathwaymentioning

confidence: 99%

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Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy

Leão¹,

Domingos

Figueiredo

et al. 2017

Urol Int

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Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the second most common cause of cancer-related mortality among men in the developed world. Conventional anti-PCa therapies include surgery, radiation, hormonal ablation, and chemotherapy. Despite increasing efforts, these therapies are not effective for patients with advanced and/or metastatic disease. In most cases, cancer therapies fail due to an incomplete depletion of tumor cells, resulting in tumor relapse. The cancer stem cell (CSC) hypothesis is an emerging model that explains many of the molecular characteristics of oncological disease as well as the tendency of cancers to relapse, metastasize, and develop resistance to conventional therapies. CSCs are a reservoir of cancer cells that exhibit properties of self-renewal and the ability to reestablish the heterogeneous tumor cell population. The existence of PCa stem cells offers a theoretical explanation for many uncertainties regarding PCa and also for treatment resistance and disease progression once clinical cure is achieved. Therapies targeting CSCs might therefore lead to more effective cancer treatments, divergent from a traditional anti-proliferative approach, based on tumor bulk reduction accompanied by CSC-specific inhibition. Here, we focus on reviewing the historical perspective as well as concepts regarding stem cells and CSCs in PCa. In addition, we will report possible strategies and new clinical approaches that address the CSC-based concept of tumorigenesis in PCa.

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“…In search of potentially interesting interactions supported by functional (present study) and biochemical (STRING) data, we noticed that PARD6G-CDC42 interaction shows closeness to Dishevelled Segment Polarity Protein 3/DVL3 and beta-catenin/CTNNB1. Both DVL3 and CTNNB1 are key mediators of the WNT signalling pathway, which plays a critical role in development and carcinogenesis 30 , 31 . On the other hand, the data suggests phenotypic closeness between PARD6G and MOB1B but also indicate that it is currently not known if the proteins directly interact in the cells.…”

Section: Resultsmentioning

confidence: 99%

Phenotype-driven identification of epithelial signalling clusters

Marques

Peltola

Kaski

et al. 2018

Sci Rep

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In metazoans, epithelial architecture provides a context that dynamically modulates most if not all epithelial cell responses to intrinsic and extrinsic signals, including growth or survival signalling and transforming oncogene action. Three-dimensional (3D) epithelial culture systems provide tractable models to interrogate the function of human genetic determinants in establishment of context-dependency. We performed an arrayed genetic shRNA screen in mammary epithelial 3D cultures to identify new determinants of epithelial architecture, finding that the key phenotype impacting shRNAs altered not only the data population average but even more noticeably the population distribution. The broad distributions were attributable to sporadic gene silencing actions by shRNA in unselected populations. We employed Maximum Mean Discrepancy concept to capture similar population distribution patterns and demonstrate here the feasibility of the test in identifying an impact of shRNA in populations of 3D structures. Integration of the clustered morphometric data with protein-protein interactions data enabled hypothesis generation of novel biological pathways underlying similar 3D phenotype alterations. The results present a new strategy for 3D phenotype-driven pathway analysis, which is expected to accelerate discovery of context-dependent gene functions in epithelial biology and tumorigenesis.

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The role of Wnt signaling pathway in carcinogenesis and implications for anticancer therapeutics

Cited by 15 publications

References 46 publications

Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis

Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis

Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy

Phenotype-driven identification of epithelial signalling clusters

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