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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
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
Processing time: 108 Days and 2.8 Hours
BACKGROUND
Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F2α synthase (PGF2α) (PGFS), an enzyme that catalyzes the production of PGF2α, is involved in the proliferation and growth of a variety of tumors. However, the role of PGFS in Oxa resistance in CRC remains unclear.
AIM
To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.
METHODS
The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels. Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance (HCT116-OxR and HCT8-OxR) and their parental cell lines (HCT116 and HCT8) to assess its influence on cell proliferation, chemoresistance, apoptosis, and DNA damage. For determination of the underlying mechanisms, CRC cells were examined for platinum-DNA adducts and reactive oxygen species (ROS) levels in the presence of a PGFS inhibitor or its products.
RESULTS
Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues. Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dose-dependent manner. Furthermore, overexpression of PGFS in parental CRC cells significantly attenuated Oxa-induced proliferative suppression, apoptosis, and DNA damage. In contrast, knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells (HCT116-OxR and HCT8-OxR) accentuated the effect of Oxa treatment in vitro and in vivo. The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa. Treatment with the PGFS-catalyzed product PGF2α reversed the effect of PGFS knockdown on Oxa sensitivity. Interestingly, PGFS inhibited the formation of platinum-DNA adducts in a PGF2α-independent manner. PGF2α exerts its protective effect against DNA damage by reducing ROS levels.
CONCLUSION
PGFS promotes resistance to Oxa in CRC via both PGF2α-dependent and PGF2α-independent mechanisms.
Core Tip: Prostaglandin F2α synthase (PGF2α) (PGFS) is an enzymatic catalyst responsible for the biosynthesis of PGF2α. Our study revealed that PGFS exerts an inhibitory effect on the generation of reactive oxygen species by means of its downstream product PGF2α, and consequently facilitates resistance to oxaliplatin in colorectal cancer. Simultaneously, PGFS suppresses the formation of platinum-DNA adducts in a manner that is not reliant on PGF2α, which is rarely reported.
