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

Area of Science:

• Natural Products Chemistry
• Cancer Biology
• Molecular Pharmacology

Background:

• Colon cancer is a leading cause of cancer-related deaths in the US, necessitating novel therapeutic strategies.
• Current colon cancer treatments have limitations, highlighting the need for new agents.
• γ-Mangostin, a bioactive compound from Garcinia mangostana, is explored for its anti-cancer properties.

Purpose of the Study:

• To investigate the potential of γ-Mangostin as a therapeutic agent for colon cancer.
• To elucidate the molecular mechanisms underlying γ-Mangostin's anti-cancer effects.
• To evaluate the efficacy of γ-Mangostin in preclinical colon cancer models.

Main Methods:

• In vitro studies using colon cancer cell lines to assess proliferation, cell cycle, apoptosis, and colonosphere formation.
• Molecular docking and Cellular Thermal Shift Assay (CETSA) to identify γ-Mangostin's molecular target.
• In vivo studies using HCT116 tumor xenografts in nude mice to evaluate tumor growth inhibition.
• Western blot analysis to assess the expression of key proteins involved in Wnt signaling and cancer stemness.

Main Results:

• γ-Mangostin suppressed colon cancer cell proliferation, colony formation, and induced cell cycle arrest and apoptosis.
• Molecular docking and CETSA identified T-Cell Factor 4 (TCF4) as a direct binding target of γ-Mangostin.
• γ-Mangostin treatment significantly inhibited tumor growth in vivo, reducing tumor volume and weight.
• The compound decreased the expression of TCF4, Wnt signaling targets (cyclin D1, c-Myc), and stem cell markers (LGR5, DCLK1, CD44).

Conclusions:

• γ-Mangostin exhibits significant anti-colon cancer activity by targeting TCF4.
• The compound effectively inhibits tumor growth and key oncogenic pathways in preclinical models.
• γ-Mangostin represents a promising natural compound for the development of novel colon cancer therapeutics.