Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Aug 15, 2020; 12(8): 877-892
Published online Aug 15, 2020. doi: 10.4251/wjgo.v12.i8.877
Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer
Yan Yan, Hong-Wei Lin, Zhuo-Nan Zhuang, Ming Li, Sen Guo
Yan Yan, Department of Operating Room, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
Hong-Wei Lin, Zhuo-Nan Zhuang, Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University, Beijing 102200, China
Ming Li, Department of General Surgery, Zouping Traditional Chinese Medicine Hospital, Zhouping 256200, Shandong Province, China
Sen Guo, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Yan Y, Lin HW, and Zhuang ZN contributed equally to this work and should be regarded as co-first authors; Yan Y and Guo S were major contributors in writing the manuscript and analyzing the data; Lin HW and Zhuang ZN made substantial contributions to the study design; Li M was a major contributor in performing the animal experiments; and all authors read and approved the final manuscript.
Supported by Beijing Tsinghua Changgung Hospital Fund, No. 12015C1042; Bethune-Excellent Surgery Fund, No. HZB-20181119-13; and Chen Xiaoping Science and Technology Development Fund, No. CXPJH11800004-021.
Institutional animal care and use committee statement: The study was reviewed and approved by the Animal Ethics Committee of Qilu Hospital of Shandong University.
Conflict-of-interest statement: All the authors have nothing to disclose.
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: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Sen Guo, PhD, Adjunct Professor, Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Street, Jinan 250012, Shandong Province, China. guosen4321@163.com
Received: May 12, 2020
Peer-review started: May 12, 2020
First decision: June 15, 2020
Revised: June 20, 2020
Accepted: July 26, 2020
Article in press: July 26, 2020
Published online: August 15, 2020
Processing time: 91 Days and 22.3 Hours
Abstract
BACKGROUND

Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B (NF-κB) pathway, resulting in the proliferation of tumor cells. Treatment with fluorouracil (5-FU) might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-κB pathway.

AIM

To detect whether interleukin (IL)-1 receptor antagonist (IL-1RA) could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells.

METHODS

Western blot analysis was performed to detect the persistent activation of the NF-κB pathway in colon cancer cell lines. Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6, IL-8, IL-17, IL-21 and TLR4 in colon cancer cell lines. We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1α feedforward loop, which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth.

RESULTS

IL-1 receptor antagonist could decrease the expression of IL-1α and IL-1β and downregulate the activity of the NF-κB pathway in Kras mutant colon cancer cells. Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line, and decreased expression of the TAK1/NF-κB and MEK pathways resulted in limited proliferation in the SW620 cell line.

CONCLUSION

Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs. IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.

Keywords: Colon carcinoma; Chemotherapy; Nuclear factor kappa-B; Interleukin-1; Proliferation; Fluorouracil

Core tip: A feedback loop between the upregulated nuclear factor kappa-B (NF-κB) pathway and interleukin (IL)-1 lads to the proliferation of cancer cells. Fluorouracil (5-FU), a chemotherapy drug used to treat colon carcinoma cells, can activate the NF-κB pathway and lead to chemotherapy resistance. IL-1 receptor antagonist combined with 5-FU has a stronger inhibitory effect on the proliferation of colon cancer cells than single 5-FU treatment due to the blockade of IL-1. This report could provide an adjuvant chemotherapy strategy for the clinic and provide a theoretical basis for neoadjuvant chemotherapy.