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Abstract
Given that colon cancer is the third most common cancer in incidence and cause of death in the United States, and current treatment modalities are insufficient, there is a need to develop novel agents. Towards this, here we focus on γ-Mangostin, a bioactive compound present in the Mangosteen (Garcinia mangostana) fruit. γ-Mangostin suppressed proliferation and colony formation, and induced cell cycle arrest and apoptosis of colon cancer cell lines. Further, γ-Mangostin inhibited colonosphere formation. Molecular docking and CETSA (Cellular thermal shift assay) binding assays demonstrated that γ-Mangostin interacts with transcription factor TCF4 (T-Cell Factor 4) at the β-catenin binding domain with the binding energy of -5.5 Kcal/mol. Moreover, γ-Mangostin treatment decreased TCF4 expression and reduced TCF reporter activity. The compound also suppressed the expression of Wnt signaling target proteins cyclin D1 and c-Myc, and stem cell markers such as LGR5, DCLK1 and CD44. To determine the effect of γ-Mangostin on tumor growth in vivo, we administered nude mice harboring HCT116 tumor xenografts with 5 mg/Kg of γ-Mangostin intraperitoneally for 21 days. γ-Mangostin treatment significantly suppressed tumor growth, with notably lowered tumor volume and weight. In addition, western blot analysis revealed a significant decrease in the expression of TCF4 and its downstream targets such as cyclin D1 and c-Myc. Together, these data suggest that γ-Mangostin inhibits colon cancer growth through targeting TCF4. γ-Mangostin may be a potential therapeutic agent for colon cancer.
Highlights
Current treatment modalities for colon cancer include surgery, radiation and chemotherapy; limitations include severe side effects and emergence of resistance
The pathway is frequently dysregulated in cancers leading to high levels of expression of target genes. β-catenin, the key factor in the pathway is regulated by the multiprotein destruction complex consisting of multiple proteins including adenomatous polyposis coli (APC), axin, www.oncotarget.com glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CSK1α) and β-transducin repeats containing protein (β-TrCP)
There are numerous Wnt signaling pathway inhibitors developed including targeting β-catenin:T-Cell Factor 4 (TCF4) interactions, while some of them may show promise, none of them have been approved by the FDA [8, 9]
Summary
Current treatment modalities for colon cancer include surgery, radiation and chemotherapy; limitations include severe side effects and emergence of resistance. The pathway is frequently dysregulated in cancers leading to high levels of expression of target genes. Β-catenin, the key factor in the pathway is regulated by the multiprotein destruction complex consisting of multiple proteins including adenomatous polyposis coli (APC), axin, www.oncotarget.com glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CSK1α) and β-transducin repeats containing protein (β-TrCP). In the absence of a Wnt signal, β-catenin is phosphorylated by casein kinase 1α (CSK1α) and APC/ Axin/GSK3-β complex and subsequently undergoes ubiquitination and proteasomal degradation. The complex becomes saturated by the phosphorylated form of β-catenin, leading to accumulation of newly synthesized β-catenin, free to translocate to the nucleus and to activate target genes [3, 4]
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