Targeting transcription factor TCF4 by ?-Mangostin, a natural xanthone.

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 ?-Mangostin, a bioactive compound present in the Mangosteen (Garcinia mangostana) fruit. ?-Mangostin suppressed proliferation and colony formation, and induced cell cycle arrest and apoptosis of colon cancer cell lines. Further, ?-Mangostin inhibited colonosphere formation. Molecular docking and CETSA (Cellular thermal shift assay) binding assays demonstrated that ?-Mangostin interacts with transcription factor TCF4 (T-Cell Factor 4) at the ?-catenin binding domain with the binding energy of -5.5 Kcal/mol. Moreover, ?-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 ?-Mangostin on tumor growth in vivo, we administered nude mice harboring HCT116 tumor xenografts with 5 mg/Kg of ?-Mangostin intraperitoneally for 21 days. ?-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 ?-Mangostin inhibits colon cancer growth through targeting TCF4. ?-Mangostin may be a potential therapeutic agent for colon cancer.

SUBMITTER: Krishnamachary B 

PROVIDER: S-EPMC6771460 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature