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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Bidirectional effects of the tryptophan metabolite indole-3-acetaldehyde on colorectal cancer
Ze Dai, Kai-Li Deng, Xiao-Mei Wang, Dong-Xue Yang, Chun-Lan Tang, Yu-Ping Zhou
Ze Dai, Xiao-Mei Wang, Dong-Xue Yang, Yu-Ping Zhou, Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
Ze Dai, Xiao-Mei Wang, Chun-Lan Tang, Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
Kai-Li Deng, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
Dong-Xue Yang, Yu-Ping Zhou, Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
Dong-Xue Yang, Yu-Ping Zhou, Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
Author contributions: Zhou YP designed and coordinated the study; Dai Z, Deng KL, and Wang XM performed the experiments, and acquired and analyzed the data; Dai Z and Tang CL interpreted the data; Dai Z, Wang XM, and Yang DX wrote the manuscript; all authors approved the final version of the article.
Supported by Zhejiang Provincial Natural Science Foundation of China, No. LTGD23C040008, No. LBY23H200006, and No. LQ22H030004.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Ningbo University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Ningbo University Experimental Animal Center.
Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Yu-Ping Zhou, PhD, Doctor, Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, No. 247 Renmin Road, Jiangbei District, Ningbo 315020, Zhejiang Province, China. fyzhouyuping@nbu.edu.cn
Received: December 17, 2023
Revised: February 13, 2024
Accepted: March 25, 2024
Published online: June 15, 2024
Processing time: 180 Days and 21.2 Hours
BACKGROUND
Colorectal cancer (CRC) has a high incidence and mortality. Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis, progression, and metastasis of CRC.
AIM
To investigate the effect of indole-3-acetaldehyde (IAAD) on CRC.
METHODS
The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines (HCT116 and DLD-1). Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests. Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide. Invasiveness was investigated using the transwell assay. Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor (AhR) downstream genes. The PharmMapper, SEA, and SWISS databases were used to screen for potential target proteins of IAAD, and the core proteins were identified through the String database.
RESULTS
IAAD reduced tumorigenesis in a syngeneic mouse model. In CRC cell lines HCT116 and DLD1, IAAD exhibited cytotoxicity starting at 24 h of treatment, while it reduced Ki67 expression in the nucleus. The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells, which may be related to the activation of AhR. IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells. At low concentrations (< 12.5 μmol/L), IAAD only exhibited cytotoxic effects without promoting cell invasion. In addition, predictions based on online databases, protein-protein interaction analysis, and molecular docking showed that IAAD can bind to matrix metalloproteinase-9 (MMP9), angiotensin converting enzyme (ACE), poly(ADP-ribose) polymerase-1 (PARP1), matrix metalloproteinase-2 (MMP2), and myeloperoxidase (MPO).
CONCLUSION
Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC; however, at high concentrations (≥ 25 μmol/L), it can also promote epithelial-mesenchymal transition and invasion in CRC cells. IAAD activates AhR and directly binds MMP9, ACE, PARP1, MMP2, and MPO, which partly reveals why it has a bidirectional effect.
Core Tip: In this study, we investigated the effect of an indole derivative of the gut microbiota, indole-3-acetaldehyde (IAAD), on colorectal cancer (CRC). The growth of tumors in a syngeneic mouse model, as well as the proliferation, apoptosis, invasion, and epithelial-mesenchymal transition of the HCT116 and DLD-1 cell lines, were observed. At low concentrations (< 12.5 μmol/L), IAAD can inhibit cell proliferation and induce cell apoptosis, but at high concentrations (≥ 25 μmol/L), it has a dual role of cytotoxicity and promotion of tumor cell invasiveness. Our results contribute to existing knowledge regarding the complex role of the gut microbiota in the occurrence and development of CRC.
