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The Antitumor and Sorafenib-resistant Reversal Effects of Ursolic Acid on Hepatocellular Carcinoma via Targeting ING5.
- Source :
-
International journal of biological sciences [Int J Biol Sci] 2024 Aug 05; Vol. 20 (11), pp. 4190-4208. Date of Electronic Publication: 2024 Aug 05 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Inhibitor of growth 5 (ING5) has been reported to be involved in the malignant progression of cancers. Ursolic acid (UA) has shown remarkable antitumor effects. However, its antitumor mechanisms regarding of ING5 in hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UA significantly suppressed the proliferation, anti-apoptosis, migration and invasion of HCC cells. In addition, ING5 expression in HCC cells treated with UA was obviously downregulated in a concentration- and time-dependent manner. Additionally, the pro-oncogenic role of ING5 was confirmed in HCC cells. Further investigation revealed that UA exerted antitumor effects on HCC by inhibiting ING5-mediated activation of PI3K/Akt pathway. Notably, UA could also reverse sorafenib resistance of HCC cells by suppressing the ING5-ACC1/ACLY-lipid droplets (LDs) axis. UA abrogated ING5 transcription and downregulated its expression by reducing SRF and YY1 expression and the SRF-YY1 complex formation. Alb/JCPyV T antigen mice were used for in vivo experiments since T antigen upregulated ING5 expression by inhibiting the ubiquitin-mediated degradation and promoting the T antigen-SRF-YY1-ING5 complex-associated transcription. UA suppressed JCPyV T antigen-induced spontaneous HCC through inhibiting ING5-mediated PI3K/Akt signaling pathway. These findings suggest that UA has the dual antitumoral functions of inhibiting hepatocellular carcinogenesis and reversing sorafenib resistance of HCC cells through targeting ING5, which could serve as a potential therapeutic strategy for HCC.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Animals
Humans
Mice
Tumor Suppressor Proteins metabolism
Tumor Suppressor Proteins genetics
Cell Line, Tumor
Cell Proliferation drug effects
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Drug Resistance, Neoplasm
Apoptosis drug effects
Phenylurea Compounds therapeutic use
Phenylurea Compounds pharmacology
Phosphatidylinositol 3-Kinases metabolism
Transcription Factors metabolism
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular metabolism
Triterpenes pharmacology
Triterpenes therapeutic use
Sorafenib pharmacology
Sorafenib therapeutic use
Liver Neoplasms metabolism
Liver Neoplasms drug therapy
Ursolic Acid
Subjects
Details
- Language :
- English
- ISSN :
- 1449-2288
- Volume :
- 20
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- International journal of biological sciences
- Publication Type :
- Academic Journal
- Accession number :
- 39247819
- Full Text :
- https://doi.org/10.7150/ijbs.97720