Indole-3-Acetic Acid as a Putative Selective AhR Modulator Counteracts Skatole-Induced Dual-Hit Toxicity in...

Area of Science:

• Microbiology
• Molecular Biology
• Cancer Research

Background:

• Colorectal cancer (CRC) incidence is rising, linked to diet-induced gut dysbiosis.
• This dysbiosis involves decreased protective indole-3-acetic acid (IAA) and increased toxic skatole (3-methylindole).
• Mechanisms of skatole-induced malignancy and IAA's counteraction are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms of skatole-induced CRC cell proliferation.
• To determine if IAA can counteract skatole's toxic effects.
• To explore IAA's potential role as a selective AhR modulator (SAhRM).

Main Methods:

• Treatment of HCT-116 CRC cells with skatole and IAA.
• Analysis of aryl hydrocarbon receptor (AhR) activity and ERK MAPK pathway activation.
• Assessment of cell proliferation and cell cycle progression.

Main Results:

• Skatole (500 µM) significantly promoted CRC cell proliferation via AhR-dependent and ERK MAPK-dependent pathways.
• IAA (250 µM) abrogated skatole-induced proliferation, restoring cell growth.
• IAA acted as a functional antagonist, reprogramming AhR signaling to uncouple MAPK phosphorylation from cell cycle progression.

Conclusions:

• IAA may function as a SAhRM, mitigating skatole's pro-proliferative effects.
• Restoring the gut IAA/skatole balance, possibly via targeting indoleacetate decarboxylase (IAD) or resistant starch, is a potential CRC prevention strategy.