Copyright
©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Deoxycholic acid induces reactive oxygen species accumulation and promotes colorectal cancer cell apoptosis through the CaMKII-Ca2+ pathway
Jia-Yan Chen, Jing-Yi Wen, Jia-Long Lin, Yan Li, Yi-Zhang Wu, Li-Qin Lou, Yong-Liang Lou, Zhi-Gui Zuo, Xiang Li
Jia-Yan Chen, Yan Li, Li-Qin Lou, Yong-Liang Lou, Xiang Li, Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Jia-Yan Chen, Jia-Long Lin, Yan Li, Yi-Zhang Wu, Li-Qin Lou, Yong-Liang Lou, Zhi-Gui Zuo, Xiang Li, Colorectal Cancer Research Center, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Jing-Yi Wen, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, Gansu Province, China
Jia-Long Lin, Yi-Zhang Wu, Zhi-Gui Zuo, Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Yan Li, Renji College, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Co-first authors: Jia-Yan Chen and Jing-Yi Wen.
Co-corresponding authors: Zhi-Gui Zuo and Xiang Li.
Author contributions: Chen JY and Wen JY contributed equally to this study as co-first authors; Zuo ZG and Li X contributed equally to this study as co-corresponding authors; Li X, Chen JY, Wen JY, and Lin JL were responsible for conceptualization and methodology; Chen JY, Wen JY, and Lin JL were responsible for resources; Chen JY, Wen JY, Lou LQ, LY, and Wu YZ were responsible for data curation; Chen JY was responsible for writing-original draft preparation; Chen JY and Lou LQ were responsible for investigation; Li X, Lou YL, and Zuo ZG was responsible for supervision; Li X, Lou YL, and Zuo ZG were responsible for writing-reviewing and editing.
Supported by the Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A); and Wenzhou Science & Technological Project, No. Y20240103.
Institutional review board statement: This study did not require ethical approval from an Institutional Review Board because it exclusively utilized commercially available, anonymized human cell lines. These cell lines were obtained from certified repositories (e.g., American Type Culture Collection), and their use complies with relevant ethical guidelines for research involving human-derived materials.
Conflict-of-interest statement: No potential conflict of interest was reported by the authors.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on 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: Xiang Li, Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, No. 1 Qiuzhen Road, Wenzhou 325035, Zhejiang Province, China.
yhx2008@163.com
Received: March 30, 2025
Revised: May 6, 2025
Accepted: June 9, 2025
Published online: August 15, 2025
Processing time: 136 Days and 17.5 Hours
BACKGROUND
Deoxycholic acid (DCA), a secondary bile acid, is associated with colorectal carcinogenesis, but its mechanisms remain unclear.
AIM
To investigate how DCA regulates apoptosis in colorectal cancer (CRC) cells.
METHODS
SW480 and DLD-1 CRC cell lines were used to investigate the mechanism of apoptosis by western blotting, flow cytometry, confocal microscopy, and other methods.
RESULTS
DCA significantly induced apoptosis, with rates increasing to 7.2% ± 1.5% in SW480 cells and 14.3% ± 0.6% in DLD-1 cells after treatment, compared to 4.7% ± 1.0% and 11.6% ± 0.8% in controls (P < 0.05). Western blot analysis showed upregulation of pro-apoptotic proteins Bax and Cleaved-PARP, with a significant increase in the Cleaved-PARP/PARP ratio (P < 0.001). DCA treatment also increased the intracellular reactive oxygen species (ROS) levels of SW480 and DLD-1 cells to 1.2-fold and 1.3-fold, respectively (P < 0.01), while the increase of mitochondrial ROS levels in these cells was statistically significant under confocal microscopy. Additionally, cytosolic and mitochondrial Ca2+ levels increased 1.3-fold and 1.2-fold, respectively, in SW480 cells (P < 0.01), and 1.1-fold and 1.1-fold, respectively, in DLD-1 cells compared with controls (P < 0.05). p-CaMKII protein levels were also elevated (P < 0.01), indicating activation of the Ca2+-CaMKII signaling pathway. Pharmacological inhibition with BAPTA-AM (1 μM) reduced mitochondrial Ca2+ accumulation and ROS levels in SW480 cells (P < 0.05), and suppressed apoptosis.
CONCLUSION
DCA activates the Ca2+-CaMKII pathway, leading to ROS-mediated apoptosis in CRC cells, providing insights for potential therapeutic targets.
Core Tip: This study reveals that deoxycholic acid (DCA) induces colorectal cancer (CRC) cell apoptosis via CaMKII-Ca2+ signaling. Using DLD-1/SW480 models, DCA elevated mitochondrial calcium and reactive oxygen species (ROS) levels, driving apoptosis. Calcium chelation reversed these effects, confirming calcium-ROS interplay as the core mechanism. The findings highlight disrupted calcium homeostasis and oxidative stress in DCA-associated carcinogenesis, providing new therapeutic targets for CRC interventions.
