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Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL), an antioxidant derived from the milk thistle plant (Silybum marianum), has been reported to exert hepatoprotective and antitumorigenic effects both in...

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Autores principales: Zhang, Song, Yang, Yang, Liang, Zhenxing, Duan, Weixun, Yang, Jian, Yan, Juanjuan, Wang, Ning, Feng, Wenqiang, Ding, Meiling, Nie, Yongzhan, Jin, Zhenxiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873967/
https://www.ncbi.nlm.nih.gov/pubmed/24386256
http://dx.doi.org/10.1371/journal.pone.0083699
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author Zhang, Song
Yang, Yang
Liang, Zhenxing
Duan, Weixun
Yang, Jian
Yan, Juanjuan
Wang, Ning
Feng, Wenqiang
Ding, Meiling
Nie, Yongzhan
Jin, Zhenxiao
author_facet Zhang, Song
Yang, Yang
Liang, Zhenxing
Duan, Weixun
Yang, Jian
Yan, Juanjuan
Wang, Ning
Feng, Wenqiang
Ding, Meiling
Nie, Yongzhan
Jin, Zhenxiao
author_sort Zhang, Song
collection PubMed
description Hepatocellular carcinoma (HCC) is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL), an antioxidant derived from the milk thistle plant (Silybum marianum), has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH) levels and total antioxidant capability (T-AOC) but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS). Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD), RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro) or DAPT (a known Notch1 inhibitor, in vivo) further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro) attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.
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spelling pubmed-38739672014-01-02 Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells Zhang, Song Yang, Yang Liang, Zhenxing Duan, Weixun Yang, Jian Yan, Juanjuan Wang, Ning Feng, Wenqiang Ding, Meiling Nie, Yongzhan Jin, Zhenxiao PLoS One Research Article Hepatocellular carcinoma (HCC) is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL), an antioxidant derived from the milk thistle plant (Silybum marianum), has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH) levels and total antioxidant capability (T-AOC) but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS). Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD), RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro) or DAPT (a known Notch1 inhibitor, in vivo) further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro) attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC. Public Library of Science 2013-12-27 /pmc/articles/PMC3873967/ /pubmed/24386256 http://dx.doi.org/10.1371/journal.pone.0083699 Text en © 2013 Zhang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhang, Song
Yang, Yang
Liang, Zhenxing
Duan, Weixun
Yang, Jian
Yan, Juanjuan
Wang, Ning
Feng, Wenqiang
Ding, Meiling
Nie, Yongzhan
Jin, Zhenxiao
Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells
title Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells
title_full Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells
title_fullStr Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells
title_full_unstemmed Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells
title_short Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells
title_sort silybin-mediated inhibition of notch signaling exerts antitumor activity in human hepatocellular carcinoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873967/
https://www.ncbi.nlm.nih.gov/pubmed/24386256
http://dx.doi.org/10.1371/journal.pone.0083699
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