Upstream eventIncreased, Reactive oxygen species
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Wnt ligand stimulation and Wnt signalling activation lead to cancer malignancy||non-adjacent||Moderate||Moderate|
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
Reactive oxygen species (ROS) increase causes beta-catenin stabilization leading to the activation. RSO may activate beta-catenin by releasing the nucleoredoxin (NRX), a thioredoxin family protein, mediated block on Dishevelled (Dvl) activity which is importantt for beta-catenin stabilization [Korswagen, 2006, Funato, 2006].
Evidence Supporting this KER
ROS which promotes the cancer progression induces several pathways including Wnt/beta-catenin pathway [Korswagen, 2006, Funato, 2006].
Lycopene, one of the major carotenoid natural products with antioxidant activity, induces apoptosis of gastric cancer cells by inhibiting nuclear translocation of beta-catenin [Kim, 20019]. ROS generated by arsenic mediates tumorigenesis through Wnt/beta-catenin pathway in which beta-catenin expression increases and activated [Zhang, 2011].
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Funato, Y., Michiue, T., Asashima, M., & Miki, H. (2006). The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt–β-catenin signalling through Dishevelled. Nature Cell Biology, 8(5), 501-508. doi:10.1038/ncb1405
Korswagen, H. C. (2006). Regulation of the Wnt/β-catenin pathway by redox signaling. Developmental Cell, 10(6), 687-688.
Kim, M., Kim, S. H., Lim, J. W., & Kim, H. (2019). Lycopene induces apoptosis by inhibiting nuclear translocation of beta-catenin in gastric cancer cells. J Physiol Pharmacol, 70(4). doi:10.26402/jpp.2019.4.11
Zhang, Z., Wang, X., Cheng, S., Sun, L., Son, Y.-O., Yao, H., . . . Shi, X. (2011). Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/β-catenin pathway in human colorectal adenocarcinoma DLD1 cells. Toxicology and Applied Pharmacology, 256(2), 114-121.