Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Feb 24, 2024; 15(2): 317-328
Published online Feb 24, 2024. doi: 10.5306/wjco.v15.i2.317
Limonin inhibits the stemness of cancer stem-like cells derived from colorectal carcinoma cells potentially via blocking STAT3 signaling
Wei-Feng Zhang, Cheng-Wei Ruan, Jun-Bo Wu, Guo-Liang Wu, Xiao-Gan Wang, Hong-Jin Chen
Wei-Feng Zhang, Jun-Bo Wu, Xiao-Gan Wang, Hong-Jin Chen, Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
Wei-Feng Zhang, Cheng-Wei Ruan, Department of Anorectal Section, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
Jun-Bo Wu, Department of Colorectal Surgery, Hengyang Central Hospital, Hengyang 421000, Hunan Province, China
Guo-Liang Wu, The First College for Clinical Medicine, Nanjing University Of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Author contributions: Zhang WF and Chen HJ are responsible for this project and designed experiments; Zhang WF, Ruan CW and Wu JB are responsible for performing experiments; Wu GL and Wang XG are responsible for data collection and data analysis; Zhang WF and Chen HJ are responsible for manuscript writing; All authors were aware of this manuscript.
Institutional animal care and use committee statement: All the animal experiments were conducted according to the Animal ethics committee in Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 2019 DW-13-02. All mouse models were housed in the SPF animal facilities (temperature 21–25 °C; humidity 50%–60%; well-ventilated cages).
Conflict-of-interest statement: No conflicts of interest was declared.
Data sharing statement: All data generated or analysed during this study are included in this published article.
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: Hong-Jin Chen, MD, Chief Doctor, Doctor, Full Professor, Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong No. 155 Road, Nanjing 210029, Jiangsu Province, China. 260789@njucm.edu.cn
Received: October 9, 2023
Peer-review started: October 9, 2023
First decision: November 23, 2023
Revised: December 6, 2023
Accepted: January 8, 2024
Article in press: January 8, 2024
Published online: February 24, 2024
ARTICLE HIGHLIGHTS
Research background

Colorectal cancer (CRC) is one of the most common types of cancer globally. In the last few decades, research efforts have been directed towards understanding the cellular and genetic mechanisms underlying the development and progression of CRC. This has led to the identification and study of a specific subset of cells within colorectal tumors, known as cancer stem cells or cancer stem-like cells (CSCs). The concept of CSCs originated in the mid-20th century but was not widely accepted until the late 1990s. The idea behind CSCs is that a small proportion of cancer cells within a tumor have stem cell-like properties, including the ability to self-renew and differentiate, which contribute to tumor initiation, progression, metastasis, and recurrence. They are also often associated with resistance to traditional cancer therapies.

Research motivation

Several studies have suggested that limonin, a natural compound found in citrus fruits, can exert anti-tumor effects. These effects appear to be due to multiple mechanisms, including the induction of apoptosis (programmed cell death), the inhibition of cancer cell proliferation, and the suppression of metastasis. Based on this, we then investigated whether it exerts suppressing effects on CSCs.

Research objectives

In this research, we evaluated the effects of limonin, a natural compound which is one of the most abundant active ingredients of Tetradium ruticarpum on stemness of CSCs derived from colorectal carcinoma cells. We also investigated the potential mechanism of limonin on stemness of CSCs.

Research methods

We performed cellular experiment to verify the suppressing effects of limonin on CSCs and performed animal experiment to verify its effects in vivo.

Research results

Limonin was found to have suppressive effects on CRC cell activities, which included cell growth, movement, invasion, colony growth and tumor development in soft agar. Even at relatively low concentrations, limonin reduced the expression of stemness markers such as Nanog and β-catenin, decreased the percentage of aldehyde dehydrogenase 1-positive CSCs, and lowered the rate of sphere formation, showing that limonin hinders stemness without cytotoxicity. Furthermore, the treatment of limonin reduced invasion and tumor development in soft agar and in nude mice. Also, limonin treatment notably inhibited the phosphorylation of STAT3 at Y705 but not S727 and had no effect on total STAT3 expression. The limonin-induced reduction in Nanog and β-catenin expression and sphere formation was noticeably offset by a pretreatment with 2 μmol/L colievlin.

Research conclusions

In summary, the findings suggest that limonin holds potential as a compound targeting CSCs, and might be utilized for tackling the recurrence and metastasis of CRC.

Research perspectives

Can limonin to be used as a chemotherpeutic sensitizor?