LBH589 Inhibits proliferation and metastasis of hepatocellular carcinoma via inhibition of gankyrin/stat3/akt pathway

Autor: Ruipeng Song, Tongsen Zheng, Hongchi Jiang, Lianxin Liu, Nishant Bhatta, Yingjian Liang, Xuan Song, Jiabei Wang, Jiaren Liu, Dalong Yin, Shangha Pan
Rok vydání: 2013
Předmět:
Cancer Research
Indoles
Gankyrin
Hepatocellular carcinoma
Apoptosis
Hydroxamic Acids
STAT3
Histones
Mice
chemistry.chemical_compound
Panobinostat
Phosphorylation
Cell Death
biology
LBH589
Liver Neoplasms
Histone deacetylase inhibitor
Acetylation
Hep G2 Cells
Cell cycle
Oncology
Caspases
Molecular Medicine
Signal Transduction
STAT3 Transcription Factor
Proteasome Endopeptidase Complex
Carcinoma
Hepatocellular
medicine.drug_class
bcl-X Protein
Mice
Nude
Antineoplastic Agents
Proto-Oncogene Proteins
medicine
Animals
Humans
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
Cell growth
Research
G1 Phase Cell Cycle Checkpoints
Xenograft Model Antitumor Assays
Molecular biology
Histone Deacetylase Inhibitors
chemistry
biology.protein
Cancer research
Protein Processing
Post-Translational
Proto-Oncogene Proteins c-akt
Zdroj: Molecular Cancer
ISSN: 1476-4598
DOI: 10.1186/1476-4598-12-114
Popis: Background Gankyrin has shown to be overexpressed in human liver cancers and plays a complex role in hepatocarcinogenesis. Panobinostat (LBH589), a new hydroxamic acid-derived histone deacetylase inhibitor has shown promising anticancer effects recently. Here, we investigated the potential of LBH589 as a form of treatment for hepatocellular carcinoma (HCC). Methods Gankyrin plasmid was transfected into HCC cells, and the cells were selected for more than 4 weeks by incubation with G418 for overexpression clones. The therapeutic effects of LBH589 were evaluated in vitro and in vivo. Cell proliferation, apoptosis, cell cycle, invasive potential, and epithelial-mesenchy-mal transition (EMT) were examined. Results LBH589 significantly inhibited HCC growth and metastasis in vitro and in vivo. Western blotting analysis indicated that LBH589 could decrease the expression of gankyrin and subsequently reduced serine-phosphorylated Akt and tyrosine-phosphorylated STAT3 expression although the total Akt and STAT3 were unaffected. LBH589 inhibited metastasis in vitro via down-regulation of N-cadherin, vimentin, TWIST1, VEGF and up-regulation of E-cadherin. LBH589 also induced apoptosis and G1 phase arrest in HCC cell lines. Ectopic expression of gankyrin attenuated the effects of LBH589, which indicates that gankyrin might play an important role in LBH589 mediated anticancer effects. Lastly, in vivo study indicated that LBH589 inhibited tumor growth and metastasis, without discernable adverse effects comparing to control group, with abrogating gankyrin/STAT3/Akt pathway. Conclusions Our results suggested that LBH589 could inhibit HCC growth and metastasis through down-regulating gankyrin/STAT3/Akt pathway. LBH589 may present itself as a novel therapeutic strategy for HCC.
Databáze: OpenAIRE
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