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Aucubin Inhibits Liver Cancer via HMGB1-mediated Inactivation of the PI3K/AKT/mTOR Signaling Pathway
Weinan Li1,2, Xuan Ma3, Yong Mei1
1Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, 550001, China.
Introduction:
Liver cancer remains one of the most aggressive and lethal malignancies worldwide,and current therapeutic efforts show limited survival benefits. Based on our previous findings that aucubin attenuates liver ischemia-reperfusion injury by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway, this study aimed to elucidate the biological functions and molecular mechanisms of aucubin in liver cancer.
Methods:
In this study, the role of aucubin in liver cancer was examined using liver cancer cell models and tumor-bearing mouse models. We evaluated whether the anti-tumor effect of aucubin is dependent on HMGB1 and its key signaling pathways. Intellectual property implications related to this small molecule are also explored.
Results:
Results revealed that aucubin effectively reduced the Epithelial-Mesenchymal Transition (EMT) behavior of liver cancer in nude mice and inhibited the migration and invasion ability of liver cancer cells. The effect of aucubin on migration and proliferation was reversed by HMGB1 overexpression in HepG2 and HCCLM3 cells. Aucubin inhibited the levels of HMGB1, RAGE, p-PI3K, p-AKT, and p-mTOR proteins in mouse tumor tissues and this change was reversed by HMGB1 overexpression.
Discussion:
We identified that aucubin exerts anti-liver cancer effects. By investigating the regulatory effects of HMGB1 overexpression and AKT agonist SC79 intervention on the HMGB1/ RAGE axis and PI3K/AKT/mTOR pathway, our findings confirmed the core role of the HMGB1/RAGE axis in aucubin's anti-tumor activity, as well as aucubin's regulation of liver cancer cell proliferation, migration, and invasion via the PI3K/AKT/mTOR pathway-ultimately mediating its anti-tumor effects.
Conclusion:
This study indicated that aucubin inhibits the proliferation, invasion, and metastasis of liver cancer by upregulating the HMGB1/RAGE axis and targeting the PI3K/AKT/mTOR signaling pathway. The results of this study highlighted the potential of aucubin as a therapeutic agent for suppressing liver cancer.
Insights
Aucubin, a natural compound, effectively suppresses liver cancer by inhibiting cell migration and invasion. It targets the HMGB1/RAGE axis and PI3K/AKT/mTOR pathway, showing potential as a novel liver cancer therapeutic.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Liver cancer is a lethal malignancy with limited treatment options.
- Previous research indicated aucubin's role in attenuating liver injury via the HMGB1/TLR-4/NF-κB pathway.
- This study investigates aucubin's function and mechanisms in liver cancer.
Purpose of the Study:
- To elucidate the anti-tumor effects and molecular mechanisms of aucubin in liver cancer.
- To determine if aucubin's anti-cancer activity is mediated by the HMGB1 signaling pathway.
- To explore the potential of aucubin as a therapeutic agent for liver cancer.
Main Methods:
- Utilized liver cancer cell and tumor-bearing mouse models to assess aucubin's anti-tumor effects.
- Investigated the dependency of aucubin's efficacy on HMGB1 and associated signaling pathways.
- Analyzed protein expression levels, including HMGB1, RAGE, p-PI3K, p-AKT, and p-mTOR.
Main Results:
- Aucubin inhibited epithelial-mesenchymal transition, migration, and invasion of liver cancer cells in vivo and in vitro.
- Overexpression of HMGB1 reversed the inhibitory effects of aucubin on migration and proliferation.
- Aucubin decreased HMGB1, RAGE, p-PI3K, p-AKT, and p-mTOR protein levels, which was reversed by HMGB1 overexpression.
Conclusions:
- Aucubin exerts anti-liver cancer effects by upregulating the HMGB1/RAGE axis.
- Aucubin targets the PI3K/AKT/mTOR pathway to inhibit liver cancer proliferation, invasion, and metastasis.
- Aucubin demonstrates significant potential as a therapeutic agent for liver cancer treatment.
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