Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. May 15, 2025; 17(5): 104522
Published online May 15, 2025. doi: 10.4251/wjgo.v17.i5.104522
Simvastatin inhibits proliferation and migration, promotes oxidative stress and ferroptosis in colon cancer
Ying Liu, Hao Ge, Zhi-Min Fan, Ting Lu, Lei He, Meng Li, Hao-Ran Zhao, Qiang Leng
Ying Liu, Ting Lu, Lei He, Meng Li, Qiang Leng, Department of Colon and Rectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
Hao Ge, Hao-Ran Zhao, Department of Traditional Chinese Medicine Surgery, First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210038, Jiangsu Province, China
Zhi-Min Fan, Department of Anorectal Medicine, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
Co-first authors: Ying Liu and Hao Ge.
Author contributions: Leng Q, Liu Y and Ge H conceived and designed the study; Liu Y, Ge H, Lu T and Zhao HR performed the literature search and data extraction; He L, Li M and Fan ZM analyzed and interpreted the data and processed them statistically; Liu Y, Ge H and Zhao HR drafted the manuscript; Leng Q and Fan ZM confirm the authenticity of all the raw data and revise the manuscript; All authors read and approved the final manuscript.
Supported by the Jiangsu Province Key Research and Development Plan (Social Development) Project, No. BE2021611.
Institutional review board statement: This study does not involve animal experimentation or human subjects, and therefore does not require approval from the Institutional Animal Care and Use Committee or the Institutional Review Board. All the experiments reported in this manuscript were conducted in accordance with standard laboratory procedures, and no ethical review was required.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
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: Qiang Leng, MM, Doctor, Department of Colon and Rectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, No. 157 Daming Road, Qinhuai District, Nanjing 210022, Jiangsu Province, China. 18115470206@163.com
Received: December 27, 2024
Revised: February 27, 2025
Accepted: April 21, 2025
Published online: May 15, 2025
Processing time: 143 Days and 1 Hours
Abstract
BACKGROUND

Colorectal cancer (CRC) is a major cause of cancer-related mortality, with limited therapeutic options for advanced stages. Simvastatin, primarily used to lower cholesterol, has shown potential as an anticancer agent. It may exert its effects by inhibiting SERPINE1, a protein implicated in CRC progression, and activating the cyclic guanosine monophosphate-protein kinase G (cGMP/PKG) signaling pathway. Given these findings, this study hypothesizes that simvastatin inhibits CRC cell proliferation and migration by downregulating SERPINE1 and activating the cGMP/PKG pathway, offering a novel therapeutic strategy for CRC management.

AIM

To study the effects of simvastatin on the function of colon cancer cells and to uncover the underlying mechanisms.

METHODS

NCM460, HCT-116, and SW620 cell lines were used for in vitro experiments with simvastatin at doses of 20 μM, 40 μM, and 80 μM. The Stitch database was used to analyze the target genes of simvastatin, whereas STRING was used to investigate SERPINE1 and its related pathways. HCT-116 and SW620 cells were transfected with single-cell RNA sequencing reveals SERPINE1 with or without Rp-8-Br-cGMP (a PKG inhibitor). Cell toxicity, proliferation, and migration were evaluated using the cell counting kit-8, colony formation, and Transwell assays, respectively. Apoptosis was analyzed via flow cytometry, and levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous ion (Fe2+) were detected using commercial kits. Real-time polymerase chain reaction and western blotting were used to analyze gene expression.

RESULTS

Simvastatin dose-dependently inhibited the proliferation and migration of HCT-116 and SW620 cells while promoting apoptosis. It downregulated Ki-67, proliferating cell nuclear antigen, MMP2, and MMP9, and upregulated Bax, particularly at higher doses. Simvastatin increased the ROS, MDA, and Fe2+ levels while decreasing the GSH levels. It downregulated SLC7A11 and ferroportin and upregulated TRF1. SERPINE1 was identified as a core target, with related genes enriched in the cGMP/PKG pathway. SERPINE1 knockdown increased GUCY1B1 and PRKG1 levels, decreased cell viability, and altered oxidative stress markers, with the effects being reversed by Rp-8-Br-cGMP.

CONCLUSION

Simvastatin effectively inhibited the proliferation and migration of colon cancer cells and promoted apoptosis through the modulation of key targets, such as SERPINE1 and the cGMP/PKG signaling pathway.

Keywords: Simvastatin; Colon cancer; Ferroptosis; SERPINE1; Cyclic guanosine monophosphate-protein kinase G pathway

Core Tip: Simvastatin significantly reduces the proliferation and migration of HCT-116 and SW620 colon cancer cell lines in a dose-dependent manner, while promoting apoptosis. Treatment with simvastatin enhances oxidative stress markers (reactive oxygen species, malondialdehyde, ferrous ion) and decreases glutathione levels, indicating its potential to induce ferroptosis in colon cancer cells through the modulation of the cyclic guanosine monophosphate-protein kinase G signaling pathway. SERPINE1 was identified as a core target of simvastatin, with its downregulation linked to increased GUCY1B1 and PRKG1 levels, suggesting a crucial role in the drug’s mechanism of action.