PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation

Area of Science:

• Gastroenterology
• Molecular Biology
• Oncology

Background:

• P21-activated kinases (PAKs) are key Rho GTPase effectors with kinase and scaffolding functions.
• Inflammation significantly impacts cellular signaling pathways, including those involved in carcinogenesis.
• The role of PAK1 in colitis-driven cancer requires further elucidation.

Purpose of the Study:

• To investigate the effects of inflammation on PAK1 signaling.
• To determine PAK1's role in colitis-associated carcinogenesis.
• To elucidate the molecular mechanisms linking PAK1, NF-κB, and PPARγ in intestinal epithelial cells.

Main Methods:

• Immunohistochemistry, immunofluorescence, and Western blot to assess PAK1 and p-PAK1 levels.
• In vivo TNFα administration in C57BL6/J mice and ex vivo organoid cultures.
• Analysis of NF-κB and PPARγ activity upon PAK1 manipulation (overexpression/silencing) and pharmacological interventions.

Main Results:

• PAK1 expression and activation were elevated at the intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer.
• TNFα treatment increased phosphorylated PAK1 (p-PAK1) in mouse intestinal villi, correlating with NF-κB activation.
• PAK1 overexpression promoted NF-κB transactivation via p65 interaction and suppressed PPARγ, while PAK1 silencing inhibited NF-κB and was influenced by PPARγ modulation.

Conclusions:

• PAK1 activation in inflammation and colitis-associated cancer drives NF-κB activity.
• PAK1 promotes carcinogenesis by suppressing PPARγ in intestinal epithelial cells.
• Targeting PAK1 signaling represents a potential therapeutic avenue for colitis-associated cancers.