<i>Hovenia dulcis</i> Suppresses the Growth of Huh7-Derived Liver Cancer Stem Cells by Inducing Necroptosis and Apoptosis and Blocking c-MET Signaling
Liver cancer stem cells (LCSCs) contribute to the initiation, metastasis, treatment resistance, and recurrence of hepatocellular carcinoma (HCC). Therefore, exploring potential anticancer agents targeting LCSCs may offer new therapeutic options to overcome HCC treatment failure. <i>Hovenia dul...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/13/1/22 |
| _version_ | 1797359029615329280 |
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| author | Mikyoung Kwon Hye Jin Jung |
| author_facet | Mikyoung Kwon Hye Jin Jung |
| author_sort | Mikyoung Kwon |
| collection | DOAJ |
| description | Liver cancer stem cells (LCSCs) contribute to the initiation, metastasis, treatment resistance, and recurrence of hepatocellular carcinoma (HCC). Therefore, exploring potential anticancer agents targeting LCSCs may offer new therapeutic options to overcome HCC treatment failure. <i>Hovenia dulcis</i> Thunberg (HDT), a tree from the buckthorn family found in Asia, exhibits various biological activities, including antifatigue, antidiabetic, neuroprotective, hepatoprotective, and antitumor activities. However, the therapeutic effect of HDT in eliminating LCSCs remains to be confirmed. In this study, we evaluated the inhibitory activity of ethanol, chloroform, and ethyl acetate extracts from HDT branches on the growth of Huh7-derived LCSCs. The ethyl acetate extract of HDT (EAHDT) exhibited the most potent inhibitory activity against the growth of Huh7 LCSCs among the three HDT extracts. EAHDT suppressed the in vitro self-renewal ability of Huh7 LCSCs and reduced tumor growth in vivo using the Huh7 LCSC-transplanted chick embryo chorioallantoic membrane model. Furthermore, EAHDT not only arrested the cell cycle in the G0/G1 phase but also induced receptor-interacting protein kinase 3/mixed-lineage kinase domain-like protein-mediated necroptosis and caspase-dependent apoptosis in Huh7 LCSCs in a concentration-dependent manner. Furthermore, the growth inhibitory effect of EAHDT on Huh7 LCSCs was associated with the downregulation of c-MET-mediated downstream signaling pathways and key cancer stemness markers. Based on these findings, we propose that EAHDT can be used as a new natural drug candidate to prevent and treat HCC by eradicating LCSCs. |
| first_indexed | 2024-03-08T15:10:46Z |
| format | Article |
| id | doaj.art-d04d385e6d1c4e20b16fd11b7cf6f471 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T15:10:46Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-d04d385e6d1c4e20b16fd11b7cf6f4712024-01-10T14:53:13ZengMDPI AGCells2073-44092023-12-011312210.3390/cells13010022<i>Hovenia dulcis</i> Suppresses the Growth of Huh7-Derived Liver Cancer Stem Cells by Inducing Necroptosis and Apoptosis and Blocking c-MET SignalingMikyoung Kwon0Hye Jin Jung1Department of Life Science and Biochemical Engineering, Graduate School, Sun Moon University, Asan 31460, Republic of KoreaDepartment of Life Science and Biochemical Engineering, Graduate School, Sun Moon University, Asan 31460, Republic of KoreaLiver cancer stem cells (LCSCs) contribute to the initiation, metastasis, treatment resistance, and recurrence of hepatocellular carcinoma (HCC). Therefore, exploring potential anticancer agents targeting LCSCs may offer new therapeutic options to overcome HCC treatment failure. <i>Hovenia dulcis</i> Thunberg (HDT), a tree from the buckthorn family found in Asia, exhibits various biological activities, including antifatigue, antidiabetic, neuroprotective, hepatoprotective, and antitumor activities. However, the therapeutic effect of HDT in eliminating LCSCs remains to be confirmed. In this study, we evaluated the inhibitory activity of ethanol, chloroform, and ethyl acetate extracts from HDT branches on the growth of Huh7-derived LCSCs. The ethyl acetate extract of HDT (EAHDT) exhibited the most potent inhibitory activity against the growth of Huh7 LCSCs among the three HDT extracts. EAHDT suppressed the in vitro self-renewal ability of Huh7 LCSCs and reduced tumor growth in vivo using the Huh7 LCSC-transplanted chick embryo chorioallantoic membrane model. Furthermore, EAHDT not only arrested the cell cycle in the G0/G1 phase but also induced receptor-interacting protein kinase 3/mixed-lineage kinase domain-like protein-mediated necroptosis and caspase-dependent apoptosis in Huh7 LCSCs in a concentration-dependent manner. Furthermore, the growth inhibitory effect of EAHDT on Huh7 LCSCs was associated with the downregulation of c-MET-mediated downstream signaling pathways and key cancer stemness markers. Based on these findings, we propose that EAHDT can be used as a new natural drug candidate to prevent and treat HCC by eradicating LCSCs.https://www.mdpi.com/2073-4409/13/1/22hepatocellular carcinomaliver cancer stem cell<i>Hovenia dulcis</i> Thunbergnecroptosisapoptosisc-MET |
| spellingShingle | Mikyoung Kwon Hye Jin Jung <i>Hovenia dulcis</i> Suppresses the Growth of Huh7-Derived Liver Cancer Stem Cells by Inducing Necroptosis and Apoptosis and Blocking c-MET Signaling Cells hepatocellular carcinoma liver cancer stem cell <i>Hovenia dulcis</i> Thunberg necroptosis apoptosis c-MET |
| title | <i>Hovenia dulcis</i> Suppresses the Growth of Huh7-Derived Liver Cancer Stem Cells by Inducing Necroptosis and Apoptosis and Blocking c-MET Signaling |
| title_full | <i>Hovenia dulcis</i> Suppresses the Growth of Huh7-Derived Liver Cancer Stem Cells by Inducing Necroptosis and Apoptosis and Blocking c-MET Signaling |
| title_fullStr | <i>Hovenia dulcis</i> Suppresses the Growth of Huh7-Derived Liver Cancer Stem Cells by Inducing Necroptosis and Apoptosis and Blocking c-MET Signaling |
| title_full_unstemmed | <i>Hovenia dulcis</i> Suppresses the Growth of Huh7-Derived Liver Cancer Stem Cells by Inducing Necroptosis and Apoptosis and Blocking c-MET Signaling |
| title_short | <i>Hovenia dulcis</i> Suppresses the Growth of Huh7-Derived Liver Cancer Stem Cells by Inducing Necroptosis and Apoptosis and Blocking c-MET Signaling |
| title_sort | i hovenia dulcis i suppresses the growth of huh7 derived liver cancer stem cells by inducing necroptosis and apoptosis and blocking c met signaling |
| topic | hepatocellular carcinoma liver cancer stem cell <i>Hovenia dulcis</i> Thunberg necroptosis apoptosis c-MET |
| url | https://www.mdpi.com/2073-4409/13/1/22 |
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