TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation

Area of Science:

• Molecular Biology
• Oncology
• Cellular Signaling

Background:

• Wnt/β-Catenin signaling is crucial for development and cancer stemness.
• TRAP1, a heat shock protein 90 (HSP90) molecular chaperone, is upregulated in colorectal cancer (CRC).
• TRAP1 is implicated in maintaining cancer stem cells by influencing the Wnt/β-Catenin pathway.

Purpose of the Study:

• To investigate the role of TRAP1 in regulating Wnt/β-Catenin signaling in colorectal cancer.
• To elucidate the mechanisms by which TRAP1 modulates Wnt/β-Catenin pathway components, including LRP5 and LRP6 receptors.

Main Methods:

• Utilized human CRC cell lines, patient-derived spheroids, and CRC specimens.
• Employed TCF/LEF Cignal Reporter Assay to assess Wnt/β-Catenin pathway activation.
• Investigated gene and protein expression, mRNA levels, promoter methylation, and protein ubiquitination/degradation.

Main Results:

• TRAP1 silencing downregulated Wnt ligand receptors LRP5 and LRP6.
• LRP5 mRNA levels decreased upon TRAP1 silencing, suggesting epigenetic regulation (promoter methylation).
• LRP6 levels were modulated post-translationally via ubiquitination/degradation, independent of mRNA changes.
• High TRAP1 expression correlated with increased active β-Catenin, LRP5, and LRP6 in human CRCs.

Conclusions:

• TRAP1 modulates Wnt/β-Catenin signaling at multiple levels in colorectal cancer.
• TRAP1's regulation of LRP5 and LRP6 contributes to cancer stemness and CRC progression.
• TRAP1 represents a potential therapeutic target for colorectal cancer by interfering with Wnt/β-Catenin pathway activation.