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Scutellarin activates IDH1 to exert antitumor effects in hepatocellular carcinoma progression
Zhao Cui1,2, Caifeng Li1, Wei Liu1
1Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, 100700, Beijing, China.
Abstract:
Isochlorate dehydrogenase 1 (IDH1) is an important metabolic enzyme for the production of α-ketoglutarate (α-KG), which has antitumor effects and is considered to have potential antitumor effects. The activation of IDH1 as a pathway for the development of anticancer drugs has not been attempted. We demonstrated that IDH1 can limit glycolysis in hepatocellular carcinoma (HCC) cells to activate the tumor immune microenvironment. In addition, through proteomic microarray analysis, we identified a natural small molecule, scutellarin (Scu), which activates IDH1 and inhibits the growth of HCC cells. By selectively modifying Cys297, Scu promotes IDH1 active dimer formation and increases α-KG production, leading to ubiquitination and degradation of HIF1a. The loss of HIF1a further leads to the inhibition of glycolysis in HCC cells. The activation of IDH1 by Scu can significantly increase the level of α-KG in tumor tissue, downregulate the HIF1a signaling pathway, and activate the tumor immune microenvironment in vivo. This study demonstrated the inhibitory effect of IDH1-α-KG-HIF1a on the growth of HCC cells and evaluated the inhibitory effect of Scu, the first IDH1 small molecule agonist, which provides a reference for cancer immunotherapy involving activated IDH1.
Insights
Scutellarin (Scu) activates isocitrate dehydrogenase 1 (IDH1), increasing α-ketoglutarate (α-KG) to inhibit hepatocellular carcinoma (HCC) growth. This IDH1 activation promotes anti-tumor immunity by downregulating HIF1a and limiting glycolysis.
Area of Science:
- Biochemistry
- Oncology
- Metabolic pathways
Background:
- Isocitrate dehydrogenase 1 (IDH1) produces α-ketoglutarate (α-KG), an intermediate with demonstrated antitumor properties.
- Targeting IDH1 for cancer therapy, particularly in hepatocellular carcinoma (HCC), remains an underexplored area.
- IDH1's role in regulating glycolysis and the tumor immune microenvironment is significant.
Purpose of the Study:
- To investigate the potential of activating IDH1 as an anticancer strategy.
- To identify small molecules that can activate IDH1 and inhibit HCC growth.
- To elucidate the mechanism by which IDH1 activation impacts HCC progression and the tumor microenvironment.
Main Methods:
- Proteomic microarray analysis to identify potential IDH1 activators.
- Biochemical assays to confirm scutellarin's (Scu) effect on IDH1 activity and α-KG production.
- In vitro and in vivo studies in HCC models to assess tumor growth inhibition, HIF1a levels, glycolysis, and immune microenvironment activation.
Main Results:
- Scutellarin (Scu) was identified as a natural small molecule that selectively modifies IDH1 at Cys297, promoting active dimer formation and increasing α-KG production.
- Scu-induced IDH1 activation led to the ubiquitination and degradation of HIF1a, subsequently inhibiting glycolysis in HCC cells.
- In vivo studies showed that Scu administration significantly increased tumor α-KG levels, downregulated the HIF1a pathway, and activated the tumor immune microenvironment, thereby inhibiting HCC growth.
Conclusions:
- IDH1 activation by Scu presents a novel therapeutic strategy against HCC by modulating the α-KG-HIF1a axis.
- The findings highlight the potential of targeting IDH1 for cancer immunotherapy, offering a new avenue for drug development.
- Scutellarin is the first identified small molecule agonist of IDH1, providing a valuable tool and reference for future research in cancer therapy.
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