Niu YR, Xiang MD, Yang WW, Fang YT, Qian HL, Sun YK. NAD+/SIRT1 pathway regulates glycolysis to promote oxaliplatin resistance in colorectal cancer. World J Gastroenterol 2025; 31(11): 100785 [PMID: 40124268 DOI: 10.3748/wjg.v31.i11.100785]
Corresponding Author of This Article
Yong-Kun Sun, PhD, Chief Doctor, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China. hsunyk@cicams.ac.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/
Ya-Ru Niu, Mi-Dan Xiang, Wen-Wei Yang, Yu-Ting Fang, Yong-Kun Sun, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Hai-Li Qian, National Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Co-first authors: Ya-Ru Niu and Mi-Dan Xiang.
Author contributions: Qian HL and Sun YK conceived the project and provided funding support for the experiments; Niu YR designed the study, performed the experiments and wrote the manuscript; Xiang MD collected the data and performed the data analysis; Yang WW and Fang YT assisted with data analysis and provided critical revisions; All the authors reviewed and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82072756; and Beijing Xisike Clinical Oncology Research Foundation, No. Y-HR2019-0285.
Institutional animal care and use committee statement: All animal experiments were approved by the Animal Control Committee of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College (NCC2024A242).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The relevant research data are included in the manuscript. Additional data will be made available upon request at hsunyk@cicams.ac.cn.
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: Yong-Kun Sun, PhD, Chief Doctor, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China. hsunyk@cicams.ac.cn
Received: August 27, 2024 Revised: December 13, 2024 Accepted: February 13, 2025 Published online: March 21, 2025 Processing time: 199 Days and 1.1 Hours
Abstract
BACKGROUND
Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells.
AIM
To investigate the role of SIRT1 in metabolic reprogramming and overcoming oxaliplatin resistance in CRC cells.
METHODS
We performed transcriptome sequencing of human CRC parental cells and oxaliplatin-resistant cells to identify differentially expressed genes. Key regulators were identified via the LINCS database. NAD+ levels were measured by flow cytometry, and the effects of SIRT1 on oxaliplatin sensitivity were assessed by MTS assays, colony formation assays, and xenograft models. Glycolytic function was measured using Western blot and Seahorse assays.
RESULTS
Salermide, a SIRT1 inhibitor, was identified as a candidate compound that enhances oxaliplatin resistance. In oxaliplatin-resistant cells, SIRT1 was downregulated, whereas γH2AX and PARP were upregulated. PARP activation led to NAD+ depletion and SIRT1 inhibition, which were reversed by PARP inhibitor treatment. The increase in SIRT1 expression overcame oxaliplatin resistance, and while SIRT1 inhibition increased glycolysis, the increase in SIRT1 inhibited glycolysis in resistant CRC cells, which was characterized by reduced expression of the glycolytic enzymes PKM2 and LDHA, as well as a decreased extracellular acidification rate. The PKM2 inhibitor shikonin inhibited glycolysis and reversed oxaliplatin resistance induced by SIRT1 inhibition.
CONCLUSION
SIRT1 expression is reduced in oxaliplatin-resistant CRC cells due to PARP activation, which in turn increases glycolysis. Restoring SIRT1 expression reverses oxaliplatin resistance in CRC cells, offering a promising therapeutic strategy to overcome drug resistance.
Core Tip: SIRT1, a NAD+-dependent deacetylase, has demonstrated anti-tumor effects in numerous studies. However, the role of SIRT1 in regulating oxaliplatin resistance remains unclear. This study found that SIRT1 expression is downregulated in oxaliplatin-resistant colorectal cancer (CRC) cell. Enhancing SIRT1 expression reverses this resistance. Mechanistically, DNA damage-induced PARP activation inhibits SIRT1 expression. The inhibition of SIRT1 promotes drug resistance in CRC cells by enhancing glycolysis. These findings highlight the critical role of SIRT1 in oxaliplatin resistance and support the potential of combining SIRT1 agonists with oxaliplatin as a therapeutic strategy to overcome CRC resistance.
