Targeting transcription factor TCF4 by γ-Mangostin, a natural xanthone

Balaji Krishnamachary, Dharmalingam Subramaniam, Prasad Dandawate, Sivapriya Ponnurangam, Pugazhendhi Srinivasan, Prabhu Ramamoorthy, Shahid Umar, Sufi Mary Thomas, Animesh Dhar, Seth Septer, Scott J. Weir, Thomas Attard, Shrikant Anant

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)5576-5591
Number of pages16
JournalOncotarget
Volume10
Issue number54
StatePublished - Sep 1 2019
Externally publishedYes

Keywords

  • Beta-catenin
  • Natural product
  • Preventive agent
  • Tumor xenograft
  • Wnt signaling

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Targeting transcription factor TCF4 by γ-Mangostin, a natural xanthone'. Together they form a unique fingerprint.

Cite this