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Mechanistic Insights into 16'-DEC-Induced Autophagy and Its Implications for Hepatocellular Carcinoma Treatment

ABSTRACT: Hepatocellular carcinoma (HCC) is a malignant tumor with a high fatality rate, characterized by a poor prognosis and a low 5-year survival rate. Although significant progress has been made in immunotherapy and targeted therapy for HCC in recent years, the overall survival benefits for patients remain very limited. Therefore, the continuous development of new targets and the screening of specific therapeutic drugs are of great significance for further developing precise treatment methods, exploring more effective combination therapies, overcoming drug resistance. In our preliminary work 272 bioactive compounds have been isolated and identified from edible and medicinal traditional Chinese medicines including Lonicera japonica, Cistanche deserticola and Artemisia capillaris. Through systematic screening, we discovered that 16'-decarbomethoxydihydrovoacamine (16'-DEC), which derived from Tabernaemontana corymbosa, can significantly inhibit hepatoma cell viability and migratory capacity. Furthermore, 16'-DEC can act in combination with lenvatinib, an approved targeted drug for HCC, to further inhibit the proliferation of hepatoma cells in vitro and in vivo. Through transcriptome sequencing, we found that 16'-DEC significantly upregulated the autophagy-related signaling pathway. Mechanism studies have validated that 16'-DEC does induce autophagy in hepatoma cells, and blocking autophagy can significantly reverse the anti-tumor activity of 16'-DEC. Furthermore, we found that 16'-DEC inhibited the activation of the mTOR signaling pathway, and molecular docking experiments indicated that 16'-DEC had a high affinity for the mTOR protein. Biochemical kinase assays confirmed 16'-DEC as a direct mTOR inhibitor, suppressing its kinase activity with an IC50 0.83 μM in cell-free systems. Taken together, these results demenstated that 16’-DEC inhibited hepatocellular carcinoma through inducing autophagy by targeting the mTOR pathway, which make it a potential therapeutic agent for HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300860 | GEO | 2025/06/26

REPOSITORIES: GEO

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Project description:Baicalein, a purified flavonoid compound with defined chemical structure extracted from the dry roots of Scutellaria radix that is a broadly used herb in China, has been proved to possess significant anti-hepatoma activity by inhibiting cell proliferation, invasion, metastasis and inducing apoptosis, autophagy via several cancer-related signaling molecules. In recent years, emerging studies have demonstrated that Chinese medicinal herbs can exert their anti-tumor effects through targeting lncRNAs，such as curcumin, camptothecin, resveratrol，paclitaxel. However, there is still no related report about the effects of baicalein on lncRNA expression profile when it exerts its inhibition on hepatoma tumor growth. To investigate whether the antitumor effect of baicalein is related to its modulation of lncRNA expression in hepatocellular carcinoma (HCC), we profiled the lncRNA expression in HCC cell line Bel-7402 treated with baicalein (0, 40, 80μM) for 24 hours using lncRNA microarray and detected the changes by comparing the lncRNA expression profile of HCC cell line Bel-7402 treated with baicalein (40 and 80 μM) and its DMSO control (0 μM). These findings suggest that modulation of lncRNA expression may be an important mechanism underlying the anti-hepatoma effects of baicalein and lay the groundwork for further investigations. To investigate whether the antitumor effect of baicalein is related to its modulation of lncRNA expression in hepatocellular carcinoma (HCC), we profiled the miRNA expression in HCC cell line Bel-7402 treated with baicalein (0, 40, 80μM) for 24 hours using miRNA microarray and detected the changes by comparing the lncRNA expression profile of HCC cell line Bel-7402 treated with baicalein (40 and 80 μM) and its DMSO control (0 μM). These findings suggest that modulation of lncRNA expression may be an important mechanism underlying the anti-hepatoma effects of baicalein and lay the groundwork for further investigations.

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Mechanistic Insights into 16'-DEC-Induced Autophagy and Its Implications for Hepatocellular Carcinoma Treatment

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