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Cited by 86Bioactive Natural Diterpenoids ResearchProtein Kinase Regulation and GTPase SignalingSesquiterpenes and Asteraceae Studies

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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

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Zhang, Z, Miao, L, Lv, C, Sun, H, Wei, S, Wang, B, Huang, C, Jiao, B·2013·Cell Death & Disease
DOI 10.1038/cddis.2013.182PMC PMC3698549
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Abstract

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 reversedWB-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) abolishedWB-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.

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Metadata

Authors
Zhang, Z., Miao, L., Lv, C., Sun, H., Wei, S., Wang, B., Huang, C., & Jiao, B.
Affiliations
  • Second Military Medical University (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Wang, B
  • Huang, C
  • Jiao, B
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2013-06-06
Volume
4
Issue
6
Pages
e657-e657
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/cddis.2013.182
PMC
PMC3698549
OpenAlex
W2091203908
Cited by
86
References
52
Citations by year
2025: 4 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 13 · 2019: 6 · 2018: 10 · 2017: 7 · 2016: 10 · 2015: 7 · 2014: 4 · 2013: 2
FWCI
3.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (973 Program, 31270403)
  • National Key Research and Development Program of China (2010CB833800)
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Bioactive Natural Diterpenoids Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Physical Sciences › Chemistry › Organic Chemistry › Sesquiterpenes and Asteraceae Studies
Keywords
hepatocellular carcinoma, G2/M cell cycle arrest, apoptosis, Ras/Raf/ERK signaling, ERK1/2 phosphorylation, JNK phosphorylation, reactive oxygen species, SMMC-7721 cells, anticancer activity
MeSH terms
Animals, Antineoplastic Agents, Enzyme Activation, Fluorouracil, Carcinoma, Hepatocellular, Heterocyclic Compounds, 4 or More Rings, Humans, Liver Neoplasms, Mice, Nude, Protein Binding, Gene Expression, Apoptosis, Reactive Oxygen Species, ras Proteins, Cell Cycle Proteins, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, raf Kinases, Mice, Membrane Potential, Mitochondrial, Hep G2 Cells, G2 Phase Cell Cycle Checkpoints

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