Jian HY, Liang ZC, Wen H, Zhang Z, Zeng PH. Shi-pi-xiao-ji formula suppresses hepatocellular carcinoma by reducing cellular stiffness through upregulation of acetyl-coA acetyltransferase 1. World J Gastrointest Oncol 2024; 16(6): 2727-2741 [PMID: 38994152 DOI: 10.4251/wjgo.v16.i6.2727]
Corresponding Author of This Article
Zhen Zhang, PhD, Doctor, Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, No. 58 Lushan Road, Changsha 410208, Hunan Province, China. zhangzhen@stu.hnucm.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
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/
Hui-Ying Jian, Zi-Cheng Liang, Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Huan Wen, Zhen Zhang, Pu-Hua Zeng, Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
Co-corresponding authors: Zhen Zhang and Pu-Hua Zeng.
Author contributions: Jian HY and Zhang Z designed the study; Jian HY and Liang ZC performed the experiments; Jian HY, Liang ZC, and Wen H collected and managed data; Jian HY analyzed data and visualizated chart, and wrote the manuscript; Zeng PH and Zhang Z co-directed and supervised this manuscript, they are co-corresponding authors of this manuscript; and all authors approved the final version of the article.
Supported bythe National Natural Science Foundation of China, No. 82074425; Hunan Science and Technology Planning Project, No. 2016SK2051 and No. 2023SK2057; and the Hunan Provincial Administration of Traditional Chinese Medicine Research Project, No. B2023089.
Institutional animal care and use committee statement: The animal study was approved by the Ethics Committee for Animal Research in Hunan University of Traditional Chinese Medicine (protocol code: LL2022070501).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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: Zhen Zhang, PhD, Doctor, Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, No. 58 Lushan Road, Changsha 410208, Hunan Province, China. zhangzhen@stu.hnucm.edu.cn
Received: January 1, 2024 Revised: March 14, 2024 Accepted: April 23, 2024 Published online: June 15, 2024 Processing time: 165 Days and 17.7 Hours
Abstract
BACKGROUND
Previous studies have shown that the Shi-pi-xiao-ji (SPXJ) herbal decoction formula is effective in suppressing hepatocellular carcinoma (HCC), but the underlying mechanisms are not known. Therefore, this study investigated whether the antitumor effects of the SPXJ formula in treating HCC were mediated by acetyl-coA acetyltransferase 1 (ACAT1)-regulated cellular stiffness. Through a series of experiments, we concluded that SPXJ inhibits the progression of HCC by upregulating the expression level of ACAT1, lowering the level of cholesterol in the cell membrane, and altering the cellular stiffness, which provides a new idea for the research of traditional Chinese medicine against HCC.
AIM
To investigate the anti-tumor effects of the SPXJ formula on the malignant progression of HCC.
METHODS
HCC cells were cultured in vitro with SPXJ-containing serum prepared by injecting SPXJ formula into wild-type mice. The apoptotic rate and proliferative, invasive, and migratory abilities of control and SPXJ-treated HCC cells were compared. Atomic force microscopy was used to determine the cell surface morphology and the Young’s modulus values of the control and SPXJ-treated HCC cells. Plasma membrane cholesterol levels in HCC cells were detected using the Amplex Red cholesterol detection kit. ACAT1 protein levels were estimated using western blotting.
RESULTS
Compared with the vehicle group, SPXJ serum considerably reduced proliferation of HCC cells, increased stiffness and apoptosis of HCC cells, inhibited migration and invasion of HCC cells, decreased plasma membrane cholesterol levels, and upregulated ACAT1 protein levels. However, treatment of HCC cells with the water-soluble cholesterol promoted proliferation, migration, and invasion of HCC cells as well as decreased cell stiffness and plasma membrane cholesterol levels, but did not alter the apoptotic rate and ACAT1 protein expression levels compared with the vehicle control.
CONCLUSION
SPXJ formula inhibited proliferation, invasion, and migration of HCC cells by decreasing plasma membrane cholesterol levels and altering cellular stiffness through upregulation of ACAT1 protein expression.
Core Tip: Cellular stiffness is a key feature of cellular biomechanics and is determined by cholesterol levels in the plasma membrane. Traditional Chinese medicine (TCM) has demonstrated good anti-tumor effects, but underlying mechanisms are not well characterized. Herein, we investigated the effects of the Shi-pi-xiao-ji (SPXJ) herbal formula on the stiffness of hepatocellular carcinoma (HCC) cells. The SPXJ formula altered the stiffness of HCC cells by decreasing plasma membrane cholesterol levels through upregulation of acetyl-coA acetyltransferase 1. Subsequently, this inhibited the invasion and metastasis of HCC cells. Our study provides a scientific basis for the clinical use of TCM preparations in the treatment of HCC.
