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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
18β-glycyrrhetinic acid regulates mitochondrial ribosomal protein L35-associated apoptosis signaling pathways to inhibit proliferation of gastric carcinoma cells
Ling Yuan, Yi Yang, Xia Li, Xin Zhou, Yu-Hua Du, Wen-Jing Liu, Lei Zhang, Lei Yu, Ting-Ting Ma, Jia-Xin Li, Yan Chen, Yi Nan
Ling Yuan, Yi Yang, Xia Li, Yu-Hua Du, Ting-Ting Ma, Jia-Xin Li, College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Xin Zhou, Yan Chen, Yi Nan, Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Wen-Jing Liu, Lei Zhang, Yan Chen, Yi Nan, Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Lei Yu, Department of Infectious Diseases, The Fourth Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Author contributions: Yuan L carried out most of the in vivo studies, analyzed the data, and wrote the manuscript; Yang Y carried out most of the in vitro experiments, wrote the manuscript, and carried out the chart-making work; Li X, Zhou X, Du YH, and Li JX were responsible for the proteomic analysis and PPI network; Ma TT performed parts of the in vivo and in vitro experiments, and conducted statistical analysis of the data; Yu L supervised the process of research and provided clinical guidance; Liu WJ and Zhang L conducted molecular biological experiments; all authors have read and approved the manuscript; Nan Y provided the conceptual and technical guidance as well as revised the manuscript critically for important intellectual content; Chen Y designed the study and revised the manuscript.
Supported by Ningxia Natural Science Foundation, No. 2020AAC03130; and Ningxia Medical University Project, No. XM2020005.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Ningxia Medical University (No. 2020-071 and No. 2021-018).
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 Ningxia Medical University (IACUC protocol number: 2019-083).
Conflict-of-interest statement: All authors declare no financial or commercial conflict of interest for this article.
Data sharing statement: All data generated or analyzed during this study are included in this paper, and further inquiries can be directed to the corresponding author (E-mail: 20080011@nxmu.edu.cn).
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: Yi Nan, MD, PhD, Professor, Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan 750004, Ningxia Hui Autonomous Region, China. 20080011@nxmu.edu.cn
Received: December 8, 2021
Peer-review started: December 8, 2021
First decision: March 11, 2022
Revised: March 24, 2022
Accepted: April 27, 2022
Article in press: April 27, 2022
Published online: June 14, 2022
ARTICLE HIGHLIGHTS
Research background
Gastric cancer (GC) is a common malignant tumor of the digestive tract in the world, with more than 1 million new cases to be expected each year since 2020. Mitochondrial ribosomal protein L35 (MRPL35) is a member of the large subunit family of mitochondrial ribosomal proteins, which plays an important role in the development of cancer.
Research motivation
At present, the treatment of gastric cancer is based mainly on surgery, chemotherapy, and radiotherapy, and the first-line treatment drugs are mainly harmful due to side effects.
Research objectives
The purpose of this study was to investigate the correlation between MRPL35 apoptosis related signaling pathway and GC.
Research methods
Cell functional indexes were determined by cell counting kit-8, flow cytometry, Transwell assay, and cell scratch assay. The effect of 18β-glycyrrhetinic acid (18β-GRA) on proliferation of gastric cancer cells was observed by BALB/C tumor-forming experiments in nude mice. Tandem mass tag labeling combined with liquid chromatography–tandem mass spectrometry were used to screen for differentially expressed proteins extracted from GC cells and control cells after 18β-GRA intervention. Moreover, STRING database was used to predict protein-protein interaction (PPI) relationships and Western blot was used to detect the expression of proteins of interest in GC cells.
Research results
18β-GRA can inhibit the proliferation of gastric cancer cells, induce apoptosis, arrest the cell cycle at G0/G1 phase, and inhibit the migration and invasion of gastric cancer cells. 18β-GRA can inhibit tumor formation in BALB/c nude mice. Compared with the control group, MRPL35 and BCL2L1 expression was significantly down-regulated and TP53 expression was up-regulated after 18β-GRA intervention. STRING analysis showed that COPS5, BAX, and BAD proteins could form PPI network with MRPL35, TP53, and BCL2L1 proteins. After 18β-GRA intervention, MRPL35, TP53, and BCL2L1 were up-regulated/down-regulated in a dose-dependent manner, as were COPS5, BAX, and BAD.
Research conclusions
18β-GRA can inhibit the proliferation of GC cells by regulating MRPL35, COPS5, TP53, BCL2L1, BAX, and BAD.
Research perspectives
MRPL35 can be used for targeted therapy of GC, and can also be used as a new biomarker for GC.
