Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2023; 29(39): 5452-5470
Published online Oct 21, 2023. doi: 10.3748/wjg.v29.i39.5452
Prostaglandin F2α synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F2α-dependent and F2α-independent mechanism
Yi-Jun Wang, Xiao-Li Xie, Hong-Qun Liu, Hui Tian, Xiao-Yu Jiang, Jiu-Na Zhang, Sheng-Xiong Chen, Ting Liu, Shu-Ling Wang, Xue Zhou, Xiao-Xu Jin, Shi-Mao Liu, Hui-Qing Jiang
Yi-Jun Wang, Xiao-Li Xie, Hui Tian, Xiao-Yu Jiang, Xue Zhou, Xiao-Xu Jin, Hui-Qing Jiang, Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Hong-Qun Liu, Liver Unit, University of Calgary, Calgary T1W0K6, Canada
Jiu-Na Zhang, Department of Gastroenterology, The Affiliated Hospital of Hebei Engineering University, Handan 056000, Hebei Province, China
Sheng-Xiong Chen, Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Ting Liu, Shu-Ling Wang, Department of Gastroenterology, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Shi-Mao Liu, Department of Gastroenterology, Hebei Youfu Hospital, Shijiazhuang 050000, Hebei Province, China
Author contributions: Wang YJ, Xie XL, and Jiang HQ conceived, and designed the study; Wang YJ, Xie XL, Zhang JN, Zhou X, Chen SX, and Liu T performed most experiments, analyzed the data, wrote the manuscript and edited the paper; Xie XL and Jiang HQ helped to supervise the study; Tian H, Jiang XY, Wang SL, Zhang JN, Jin XX, and Liu SM helped to perform the experiments and analyzed the data; Xie XL, Liu HQ, and Jiang HQ helped to edit the paper; All authors have read and approved the final manuscript.
Supported by the S and T Program of Hebei, No. 22377704D; Medical Science Research Project of Hebei Province, No. 20190510; Postgraduate’s Innovation Fund Project of Hebei Province, No. CXZZBS2021077.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Second Hospital of Hebei Medical University (No. 2021-R441).
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (The Animal Experiments Inspectorate, Second Hospital of Hebei Medical University; protocol no. 2022-AE010, The Institutional Animal Care and Use Committee at the Second Hospital of Hebei Medical University, Hebei Province, China).
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest in our study.
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: Hui-Qing Jiang, Doctor, Chief Physician, Director, Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang 050000, Hebei Province, China. jianghuiqing1959@sina.com
Received: July 3, 2023
Peer-review started: July 3, 2023
First decision: August 25, 2023
Revised: September 14, 2023
Accepted: September 26, 2023
Article in press: September 26, 2023
Published online: October 21, 2023
ARTICLE HIGHLIGHTS
Research background

Chemoresistance is a major obstacle in colorectal cancer (CRC) therapy. Therefore, characterizing mechanisms of chemoresistance is beneficial to improve the treatment efficacy and survival rate of CRC patients. In this study, we identify the role and potential mechanism of prostaglandin F2α synthase (PGF2α) (PGFS) in drug resistance to CRC, providing a novel therapeutic target against cancer drug resistance in the treatment of CRC.

Research motivation

The new theory of this study is that PGFS resistance to oxaliplatin (Oxa) has two effects, one is to reduce the production of reactive oxygen species (ROS) through the generation of PGF2α products, and the other is the direct protective effect of PGFS on CRC nucleus. The new method in this study is the application of comet experiment to detect DNA damage, and the other is the application of inductively coupled plasma mass spectrometry (ICP-MS) to directly detect the platinum content of DNA in the nucleus, so as to directly detect the effect of PGFS on the binding of platinum and DNA.

Research objectives

This study was designed to exploit the function and mechanism of PGFS in chemoresistance in CRC. Our study reveals the different ways in which PGFS promotes chemoresistance in CRC, and provides a potential target for predicting and reversing chemoresistance of CRC.

Research methods

The expression level of PGFS is assessed in 37 pairs of CRC tissues and para-cancer tissues by as detected by quantitative polymerase chain reaction and western blot. We examined the influence of PGFS overexpression or knockdown in acquired Oxa-resistant CRC cell lines (HCT116-OxR and HCT8-OxR) and their parental cell lines (HCT116 and HCT8). In order to analyze how PGFS affects colon cancer cell proliferation, A cholecystokinin octapeptide assay was utilized to determine the half-inhibitory concentration value of the cells, a plate clone formation assay was used to determine the clonogenesis ability, and an analysis of proliferating cell nuclear antigen expression was performed to determine the growth rate. Transferase dUTP nick end labeling and Annexin V/propidium iodide stainings, as well as the apoptotic markers cleaved-poly ADP-ribose polymerase and cleaved-caspase 3, were used to detect apoptosis. Western blot and cellular immunofluorescence were used to detect the expression and morphology of the DNA damage marker γ-H2AX. The DNA damage was detected by single-cell gel electrophoresis. Indomethacin, an inhibitor of prostaglandin synthase of PGFS, was used to elucidate the underlying mechanisms. Rescue experiments were conducted by introducing PGF2α, the product of PGFS, subsequent to the knockdown of PGFS. The platinum-DNA adducts were quantified using ICP-MS, and intracellular ROS levels were measured using a kit for measuring reactive oxygen species.

Research results

We found that PGFS reduced the production of ROS through its downstream product PGF2α, and thereby promotes Oxa resistance in CRC, meanwhile, it inhibited the formation of platinum-DNA adducts in a PGF2α-independent manner. The suppressive role of PGFS in the formation of platinum-DNA adducts has never been reported before. However, some questions need to be further clarified, for example, by what mechanism does PGFS suppress the formation of platinum-DNA adducts?

Research conclusions

This study aims to explore the relationship between PGFS and the occurrence and development of CRC, and the relationship between PGFS and Oxa resistance in CRC as well as the related mechanisms. In the future, it is hoped to predict whether patients with CRC are resistant to Oxa by detecting PGFS genes.

Research perspectives

Further work will be needed to clarify the function of PGFS in the nucleus and its mechanisms of action. Moreover, the inhibition mechanism of PGFS in the formation of platinum-DNA adducts needs to be further elucidated.