Zhang WF, Ruan CW, Wu JB, Wu GL, Wang XG, Chen HJ. Limonin inhibits the stemness of cancer stem-like cells derived from colorectal carcinoma cells potentially via blocking STAT3 signaling. World J Clin Oncol 2024; 15(2): 317-328 [PMID: 38455137 DOI: 10.5306/wjco.v15.i2.317]
Corresponding Author of This Article
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
Research Domain of This Article
Oncology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
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
Abstract
BACKGROUND
Limonin is one of the most abundant active ingredients of Tetradium ruticarpum. It exerts antitumor effects on several kinds of cancer cells. However, whether limonin exerts antitumor effects on colorectal cancer (CRC) cells and cancer stem-like cells (CSCs), a subpopulation responsible for a poor prognosis, is unclear.
AIM
To evaluate the effects of limonin on CSCs derived from CRC cells.
METHODS
CSCs were collected by culturing CRC cells in serum-free medium. The cytotoxicity of limonin against CSCs and parental cells (PCs) was determined by cholecystokinin octapeptide-8 assay. The effects of limonin on stemness were detected by measuring stemness hallmarks and sphere formation ability.
RESULTS
As expected, limonin exerted inhibitory effects on CRC cell behaviors, including cell proliferation, migration, invasion, colony formation and tumor formation in soft agar. A relatively low concentration of limonin decreased the expression stemness hallmarks, including Nanog and β-catenin, the proportion of aldehyde dehydrogenase 1-positive CSCs, and the sphere formation rate, indicating that limonin inhibits stemness without presenting cytotoxicity. Additionally, limonin treatment inhibited invasion and tumor formation in soft agar and in nude mice. Moreover, limonin treatment significantly inhibited the phosphorylation of STAT3 at Y705 but not S727 and did not affect total STAT3 expression. Inhibition of Nanog and β-catenin expression and sphere formation by limonin was obviously reversed by pretreatment with 2 μmol/L colievlin.
CONCLUSION
Taken together, these results indicate that limonin is a promising compound that targets CSCs and could be used to combat CRC recurrence and metastasis.
Core Tip: Colorectal cancer (CRC) is recognized worldwide as one of the most common malignancies and frequently leads to cancer-related death and the subpopulation termed cancer stem-like cell contributes critically to recurrence and metastasis. However, therapeutic molecule or strategy targeting to this subpopulation is still largely unknown. Here, we introduce Limonin, is one of the most abundant active ingredients of Tetradium ruticarpum, as a promising molecule targeting to cancer stem-like cells for CRC therapy.
