Activation of the TLR4-JNK but not the TLR4-ERK pathway induced by indole-3-acetic acid exerts anti-proliferative effects on Caco-2 cells

Abstract

We previously found that indole-3-acetic acid (IAA) produced from tryptophan by gut microbiota decreases the expression of tumor necrosis factor alpha (TNFα), which is implicated in the pathogenesis of colorectal cancer (CRC). The present study aimed to determine IAA involvement in the proliferation of CRC-derived Caco-2 cells. Cell proliferation was suppressed by IAA, whereas IAA-induced aryl hydrocarbon receptor (AhR) activation had no impact. IAA activated extracellular signal-related (ERK) and c-Jun N-terminal (JNK) kinases, but not p38. Toll-like receptor 4 (TLR4) may be required to activate ERK and JNK, but only the TLR4-JNK pathway might elicit the anti-proliferative effects of IAA. Thus, IAA may be a ligand for TLR4 that contributes to inhibiting CRC cell proliferation by activating TLR4-mediated JNK. Because IAA did not induce cytotoxicity, inhibiting cell cycle progression might affect the anti-proliferative capacity of IAA. Therefore, colonic IAA accumulation might help to prevent CRC development and progression.

Untargeted metabolomics in gastric and colorectal cancer patients – preliminary results

“…For instance, in case of indole-3-acetic acid and tryptophan, the levels are higher in colorectal cancer than in gastric cancer. Indole-3-acetic acid is a tryptophan metabolite produced by gut microbiota according to the following pathway in intestinal epithelial cells: (1) ingested dietary protein, (2) tryptophan, (3) intestinal microbiota, (4) indole-3-acetic acid ( Seo and Wargo, 2023 ; Tomii et al., 2023 ). This result can be associated with different overall characteristics of gut microbiota in particular types of cancer, i.e.…”

Gut microbiome: decision-makers in the microenvironment of colorectal cancer

“…The gut microbiota metabolizes tryptophan to generate Indole-3-acetic acid (3-IAA), which effectively downregulates the expression of TNF-α. This reduction in TNF-α expression is attributed to the enzymatic conversion of tryptophan, highlighting the microbiota’s significant role in modulating inflammatory responses ( Tomii et al., 2023 ). Furthermore, the metabolization of tryptophan by the bacterial flora results in the production of indole, which exerts regulatory control over mucosal immunity by activating receptors associated with polycyclic aromatic hydrocarbons ( Lavelle and Sokol, 2020 ; Hezaveh et al., 2022 ).…”

“…The gut microbiota metabolizes tryptophan to generate Indole-3-acetic acid (3-IAA), which effectively downregulates the expression of TNF-a. This reduction in TNF-a expression is attributed to the enzymatic conversion of tryptophan, highlighting the microbiota's significant role in modulating inflammatory responses (Tomii et al, 2023).…”

Tryptophan metabolism in digestive system tumors: unraveling the pathways and implications

“…Melatonin inhibits cell proliferation by inducing the G2/M phase arrest [ 76 ]. IAA inhibits tumor progression by activating the Toll-like receptor 4 (TLR4)-c-Jun N-terminal kinase (JNK) pathway in CRC [ 73 ]. Melatonin significantly downregulates endothelin-1 levels, inhibiting CRC malignant phenotypes by reducing forkhead transcription factor-1 (FOXO-1) and nuclear factor-kappabeta (NF-κβ) levels [ 76 ].…”