1. Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response.
- Author
-
Xiao MY, Pei WJ, Li S, Li FF, Xie P, Luo HT, Hyun Yoo H, and Piao XL
- Subjects
- Humans, Animals, Mice, Dose-Response Relationship, Drug, Molecular Structure, Drug Screening Assays, Antitumor, Apoptosis drug effects, Structure-Activity Relationship, Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Agents, Phytogenic chemistry, Mice, Inbred BALB C, Mice, Nude, Liver Neoplasms, Experimental drug therapy, Liver Neoplasms, Experimental pathology, Liver Neoplasms, Experimental metabolism, Plant Extracts, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular metabolism, Gynostemma chemistry, Liver Neoplasms drug therapy, Liver Neoplasms pathology, Liver Neoplasms metabolism, Sterol Regulatory Element Binding Protein 2 metabolism, Sterol Regulatory Element Binding Protein 2 antagonists & inhibitors, Cell Proliferation drug effects
- Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor tissues. These findings highlight gypenoside L as a promising agent for targeting cholesterol metabolism in HCC while emphasizing the effectiveness of regulating the SREBP2-HMGCS1 axis as a therapeutic strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF