Usnic Acid Targets 14-3-3 Proteins and Suppresses Cancer Progression by Blocking Substrate Interaction

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Usnic acid (UA), a lichen-derived secondary metabolite, exhibits demonstrated anticancer properties.
• The precise molecular mechanisms underlying UA's anticancer effects require further elucidation.

Purpose of the Study:

• To identify the specific protein target of usnic acid (UA).
• To elucidate the mechanism by which UA exerts its anticancer effects, particularly in colorectal cancer.

Main Methods:

• Affinity chromatography using a UA-linker-Affi-Gel molecule to identify UA-binding proteins.
• Analysis of UA's impact on colorectal cancer cell processes including invasion, cell cycle, and metabolism.
• Investigation of UA's effects on key signaling pathways (Akt/mTOR, JNK, STAT3, NF-κB, AP-1).
• Utilizing a peptide inhibitor of 14-3-3 to validate the target's role.

Main Results:

• Usnic acid (UA) was identified to bind specifically to the 14-3-3 protein.
• UA binding to 14-3-3 induced the degradation of proteasomal and autophagosomal proteins.
• UA's interaction with 14-3-3 isoforms modulated colorectal cancer cell invasion, cell cycle, aerobic glycolysis, and mitochondrial biogenesis.
• UA significantly affected multiple cancer-related signaling pathways, including Akt/mTOR, JNK, STAT3, NF-κB, and AP-1.
• A 14-3-3 peptide inhibitor abrogated UA's activity and effects.

Conclusions:

• Usnic acid (UA) functions by binding to 14-3-3 isoforms.
• This interaction leads to the suppression of colorectal cancer progression through the modulation of 14-3-3 targets and downstream signaling pathways.