Ursodeoxycholic Acid Alleviates DSS/AOM-Induced Colorectal Cancer in Mice by Inhibiting PI3K/Akt/mTOR Signaling...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Ursodeoxycholic acid (UDCA) shows promise for colorectal cancer (CRC) treatment due to its anti-inflammatory and immunomodulatory effects.
• The exact molecular mechanisms underlying UDCA's anti-CRC activity require further elucidation.

Purpose of the Study:

• To investigate the molecular targets and mechanisms of UDCA in colorectal cancer (CRC).
• To evaluate UDCA's impact on the gut microenvironment in a colitis-associated cancer model.

Main Methods:

• An integrative approach combining network pharmacology, molecular docking, and in vivo validation using an AOM/DSS-induced mouse model.
• Analysis of the PI3K/Akt/mTOR signaling pathway and epidermal growth factor receptor (EGFR) interactions.
• Assessment of changes in the tumor microenvironment, including cytokine levels, metabolic gene expression, and gut microbiota composition.

Main Results:

• UDCA significantly reduced colitis-associated tumorigenesis and tumor burden in mice.
• UDCA inhibited the PI3K/Akt/mTOR signaling pathway, with EGFR identified as a direct upstream target.
• UDCA treatment modulated the tumor microenvironment by suppressing pro-inflammatory cytokines, regulating metabolic genes (CYP19A1, HMGCR), and promoting gut microbiota homeostasis.

Conclusions:

• UDCA exerts anti-tumor effects in CRC primarily by inhibiting the EGFR-mediated PI3K/Akt/mTOR pathway.
• UDCA partially restores the intestinal immune-metabolic microenvironment, contributing to its therapeutic potential.
• These findings provide novel mechanistic insights into UDCA's efficacy for colorectal cancer (CRC) treatment.