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Wentilactone B induces G2/M phase arrest and apoptosis via the Ras/Raf/MAPK signaling pathway in human hepatoma SMMC-7721 cells
Zhang, Z.1; Miao, L.1; Lv, C.1; Sun, H.2; Wei, S.1; Wang, B.2; Huang, C.1; Jiao, B.1; Huang, C
2013-06-01
Source PublicationCELL DEATH & DISEASE
ISSN2041-4889
Volume4Pages:e657
SubtypeArticle
AbstractHepatocellular carcinoma (HCC) is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Wentilactone B (WB), a tetranorditerpenoid derivative extracted from the marine algae-derived endophytic fungus Aspergillus wentii EN-48, has been shown to trigger apoptosis and inhibit metastasis in HCC cell lines. However, the mechanisms of its antitumor activity remain to be elucidated. We report here that WB could significantly induce cell cycle arrest at G2 phase and mitochondrial-related apoptosis, accompanying the accumulation of reactive oxygen species (ROS). Additionally, treatment with WB induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38 MAP kinase. Among the pathway inhibitors examined, only SP600125 (JNK inhibitor) markedly reversed WB-induced apoptosis, and only U0126 (ERK inhibitor) significantly blocked WB-triggered G2 phase arrest. We also found that WB treatment increased both Ras and Raf activation, and transfection of cells with dominant-negative Ras (RasN17) abolished WB-induced apoptosis and G2 phase arrest in SMMC-7721 cells. Furthermore, the results of inverse docking (INVDOCK) analysis suggested that WB could bind to Ras-GTP, and the direct binding affinity was also confirmed by surface plasmon resonance (SPR). Finally, in vivo, WB suppressed tumor growth in mouse xenograft models. Taken together, these results indicate that WB induced G2/M phase arrest and apoptosis in human hepatoma SMMC-7721 cells via the Ras/Raf/ERK and Ras/Raf/JNK signaling pathways, and this agent may be a potentially useful compound for developing anticancer agents for HCC.; Hepatocellular carcinoma (HCC) is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Wentilactone B (WB), a tetranorditerpenoid derivative extracted from the marine algae-derived endophytic fungus Aspergillus wentii EN-48, has been shown to trigger apoptosis and inhibit metastasis in HCC cell lines. However, the mechanisms of its antitumor activity remain to be elucidated. We report here that WB could significantly induce cell cycle arrest at G2 phase and mitochondrial-related apoptosis, accompanying the accumulation of reactive oxygen species (ROS). Additionally, treatment with WB induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38 MAP kinase. Among the pathway inhibitors examined, only SP600125 (JNK inhibitor) markedly reversed WB-induced apoptosis, and only U0126 (ERK inhibitor) significantly blocked WB-triggered G2 phase arrest. We also found that WB treatment increased both Ras and Raf activation, and transfection of cells with dominant-negative Ras (RasN17) abolished WB-induced apoptosis and G2 phase arrest in SMMC-7721 cells. Furthermore, the results of inverse docking (INVDOCK) analysis suggested that WB could bind to Ras-GTP, and the direct binding affinity was also confirmed by surface plasmon resonance (SPR). Finally, in vivo, WB suppressed tumor growth in mouse xenograft models. Taken together, these results indicate that WB induced G2/M phase arrest and apoptosis in human hepatoma SMMC-7721 cells via the Ras/Raf/ERK and Ras/Raf/JNK signaling pathways, and this agent may be a potentially useful compound for developing anticancer agents for HCC.
KeywordWentilactone b Smmc-7721 Cells Cell Cycle Arrest Apoptosis Mapk Pathway
Subject AreaCell Biology
DOI10.1038/cddis.2013.182
URL查看原文
Indexed BySCI
Language英语
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000321111700008
Citation statistics
Cited Times:44[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/16677
Collection实验海洋生物学重点实验室
Corresponding AuthorHuang, C
Affiliation1.Second Mil Med Univ, Fac Basic Med, Dept Biochem & Mol Biol, Shanghai 200433, Peoples R China
2.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao, Peoples R China
Recommended Citation
GB/T 7714
Zhang, Z.,Miao, L.,Lv, C.,et al. Wentilactone B induces G2/M phase arrest and apoptosis via the Ras/Raf/MAPK signaling pathway in human hepatoma SMMC-7721 cells[J]. CELL DEATH & DISEASE,2013,4:e657.
APA Zhang, Z..,Miao, L..,Lv, C..,Sun, H..,Wei, S..,...&Huang, C.(2013).Wentilactone B induces G2/M phase arrest and apoptosis via the Ras/Raf/MAPK signaling pathway in human hepatoma SMMC-7721 cells.CELL DEATH & DISEASE,4,e657.
MLA Zhang, Z.,et al."Wentilactone B induces G2/M phase arrest and apoptosis via the Ras/Raf/MAPK signaling pathway in human hepatoma SMMC-7721 cells".CELL DEATH & DISEASE 4(2013):e657.
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