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β-catenin activation leads to Snail, Zeb, Twist activation
Key Event Relationship Overview
AOPs Referencing Relationship
|Homo sapiens||Homo sapiens||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Beta-catenin activation, of which mechanism include the stabilization of the dephosphorylated beta-catenin and translocation of beta-catenin into the nucleus, induce the formation of beta-catenin-TCF complex and transcription of transcription factors such as Snail, Zeb and Twist (Clevers & Nusse, 2012) (Ahmad et al., 2012; Pearlman, Montes de Oca, Pal, & Afaq, 2017; Sohn et al., 2019; W. Yang et al., 2019).
Evidence Supporting this KER
The treatment of human gastric cancer cells with INC280, which inhibits c-MET overexpressed in diffuse-type gastric cancer with poor prognosis, shows downregulation in beta-catenin and Snail expression, (Sohn et al., 2019).
The treatment with garcinol, a polyisoprenylated benzophenone derivative that is obtained from Garcinia indica extract, induced ZEB1 and ZEB2 down-regulation, increase in phosphorylated beta-catenin and decrease in nuclear beta-catenin in human breast cancer cells (Ahmad et al., 2012).
Sortilin, a member of the Vps10p sorting receptor family which is highly expressed in high-glade malignant glioma, positively regulates GSK-3beta/beta-catenin/Twist signaling pathway in glioblastoma (W. Yang et al., 2019).
Uncertainties and Inconsistencies
It is possible that the inhibition of ZEB1 and ZEB2 by garcinol treatment is caused by down-regulation of NFkappaB and Wnt/beta catenin signaling (Ahmad et al., 2012).
The treatment with AF38469, a sortilin inhibitor, in 0, 100, 200, 400, 800, and 1600 nM concentration inhibited beta-catenin and Twist expression dose-depenently in human glioblastoma cells (W. Yang et al., 2019).
The treatment with 25 mM of garcinol for 48 hours induced increase in phosphorylated beta-catenin and decreased nuclear beta-catenin protein and ZEB1/ZEB2 mRNA in human breast cancer cells (Ahmad et al., 2012).
The treatment with AF38469, a sortilin inhibitor, for 0, 2, 4, 8, 16, or 24 hours shows that the expression of beta-catenin and Twist decrease in 8 hours followed by the subsequent decrease in 16 and 24 hours in human gliobastoma cells (W. Yang et al., 2019).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
The inhibited expression of phosphorylated GSK3beta, beta-catenin and Twist by sortilin inhibition is reversed by GSK3beta inhibition. Furthermore, twist overexpression by lentivirus increased the inhibited expression of N-cadherin, MMP9 and vimentin and reverses the inhibitory effect of AF38469 on sortilin, which suggests that sortilin induces glioblastoma invasion mainly via GSK3beta/beta-catenin/Twist induced mesenchymal transition (W. Yang et al., 2019).
Domain of Applicability
Ahmad, A., Sarkar, S. H., Bitar, B., Ali, S., Aboukameel, A., Sethi, S., . . . Sarkar, F. H. (2012). Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. Mol Cancer Ther, 11(10), 2193-2201. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22821148. doi:10.1158/1535-7163.MCT-12-0232-T
Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22682243. doi:10.1016/j.cell.2012.05.012
Pearlman, R. L., Montes de Oca, M. K., Pal, H. C., & Afaq, F. (2017). Potential therapeutic targets of epithelial-mesenchymal transition in melanoma. Cancer Lett, 391, 125-140. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28131904. doi:10.1016/j.canlet.2017.01.029
Sohn, S. H., Kim, B., Sul, H. J., Kim, Y. J., Kim, H. S., Kim, H., . . . Zang, D. Y. (2019). INC280 inhibits Wnt/beta-catenin and EMT signaling pathways and its induce apoptosis in diffuse gastric cancer positive for c-MET amplification. BMC Res Notes, 12(1), 125. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30871613. doi:10.1186/s13104-019-4163-x
Yang, W., Wu, P. F., Ma, J. X., Liao, M. J., Wang, X. H., Xu, L. S., . . . Yi, L. (2019). Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3beta/beta-catenin/twist pathway. Cell Death Dis, 10(3), 208. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30814514. doi:10.1038/s41419-019-1449-9