Cholesterol-targeting Wnt-β-catenin signaling inhibitors for colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Most colorectal cancer (CRC) cases involve adenomatous polyposis coli (APC) truncation, leading to abnormal Wnt-β-catenin signaling.
• Current targeted therapies for APC-truncated CRC are limited due to an incomplete understanding of the underlying mechanisms.

Purpose of the Study:

• To elucidate the mechanism by which APC truncation drives colorectal cancer.
• To identify and evaluate novel therapeutic targets for APC-truncated CRC.

Main Methods:

• Investigated cholesterol levels in the inner plasma membrane leaflet of APC-truncated CRC cells.
• Examined the interaction between Dishevelled (Dvl) and cholesterol in Wnt signalosome formation.
• Tested the efficacy of cholesterol-Dvl interaction inhibitors in vitro and in vivo using a xenograft mouse model.

Main Results:

• Elevated inner plasma membrane cholesterol levels were observed in all tested APC-truncated CRC cells.
• Cholesterol-Dvl interaction was identified as a driver of Wnt-independent signalosome formation.
• Inhibitors targeting cholesterol-Dvl interactions effectively suppressed β-catenin signaling and viability in cancer cells, with minimal impact on normal cells.
• In vivo studies demonstrated tumor suppression in a xenograft model without intestinal toxicity.

Conclusions:

• Cholesterol-Dvl-β-catenin signaling axis represents a promising therapeutic target for APC-truncated colorectal cancer.
• Targeting this axis offers a potentially safe and effective treatment strategy for the most common form of CRC.