Primary liver cancer is the third leading cause of cancer death in the world, and the lack of effective treatments is the main reason for the high mortality. Corosolic acid (CA) has been proved to have antitumor activity. In this study, we found that CA can sensitize liver cancer cells to ferroptosis, which is a regulated form of cell death characterized by iron-dependent lipid peroxides reaching lethal levels. Here, we revealed that CA can inhibit glutathione (GSH) synthesis via HERPUD1, decreasing the cellular GSH level and causing liver cancer cells to become more sensitive to ferroptosis. Mechanistically, further studies found that HERPUD1 reduced the ubiquitination of the GSS-associated E3 ubiquitin ligase MDM2, which promoted ubiquitination of GSS, thereby inhibiting GSH synthesis to increase ferroptosis susceptibility. Importantly, a mouse xenograft model also demonstrated that CA inhibits tumor growth via HERPUD1. Collectively, our findings suggesting that CA is a candidate component for the development of treatments against liver cancer.
Hepatocellular carcinoma (HCC) is a common cancer with very limited therapeutic options. Our previous study revealed that corosolic acid inhibited HCC proliferation and enhanced chemotherapy sensitivity. This study set out to identify the differentially expressed proteins of corosolic acid in the treatment of liver cancer cells, providing molecular targets for targeted therapy of liver cancer in the future. First, data on potential therapeutic targets regulated by corosolic acid were collected using proteomics. The enrichment analysis of GO and KEGG was used to identify the differentially expressed proteins. Differentially expressed genes (DEGs) from The Cancer Genome Atlas (TCGA) liver cancer dataset were analyzed by using the DESeq2 R package. Then,databases such as GEPIA2, Human Protein Atlas, and UALCAN were used to validate the differential expression of DEGs and the prognostic relevance to patients. Finally, experiments were carried out to verify the effect of corosolic acid on hepatocellular carcinoma cell phenotype and the modulation of the screened target proteins. This study will help to understand the molecular changes of HCC after corosolic acid treatment, which will help to find new targets and design effective chemotherapy regimens for future HCC treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.