Targeting transcription factor TCF4 by γ-Mangostin, a natural xanthone
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Balaji Krishnamachary1, Dharmalingam Subramaniam1, Prasad Dandawate1, Sivapriya Ponnurangam1, Pugazhendhi Srinivasan1, Prabhu Ramamoorthy1, Shahid Umar2, Sufi Mary Thomas3, Animesh Dhar1, Seth Septer4, Scott J. Weir1, Thomas Attard5 and Shrikant Anant1
1 Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
2 Department of General Surgery, University of Kansas Medical Center, Kansas City, KS, USA
3 Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS, USA
4 Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Colorado, Aurora, CO, USA
5 Department of Pediatrics, Division of Gastroenterology, Children’s Mercy Hospital, Kansas City, KS, USA
Keywords: Wnt signaling; beta-catenin; natural product; tumor xenograft; preventive agent
Received: April 10, 2019 Accepted: July 17, 2019 Published: September 24, 2019
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.
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