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    Negative regulation of signal transducer and activator of transcription-3 signalling cascade by lupeol inhibits growth and induces apoptosis in hepatocellular carcinoma cells

    219270_142581_bjc2014422a.pdf (1.599Mb)
    Access Status
    Open access
    Authors
    Siveen, K.
    Nguyen, A.
    Lee, J.
    Li, F.
    Singh, S.
    Kumar, Alan Prem
    Low, G.
    Jha, S.
    Tergaonkar, V.
    Ahn, K.
    Sethi, G.
    Date
    2014
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Siveen, K. and Nguyen, A. and Lee, J. and Li, F. and Singh, S. and Kumar, A.P. and Low, G. et al. 2014. Negative regulation of signal transducer and activator of transcription-3 signalling cascade by lupeol inhibits growth and induces apoptosis in hepatocellular carcinoma cells. British Journal of Cancer. 111: pp. 1327-1337.
    Source Title
    British Journal of Cancer
    DOI
    10.1038/bjc.2014.422
    ISSN
    0007-0920
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/9603
    Collection
    • Curtin Research Publications
    Abstract

    Background: Constitutive activation of signal transducer and activator of transcription signalling 3 (STAT3) has been linked with survival, proliferation and angiogenesis in a wide variety of malignancies including hepatocellular carcinoma (HCC). Methods: We evaluated the effect of lupeol on STAT3 signalling cascade and its regulated functional responses in HCC cells. Results: Lupeol suppressed constitutive activation of STAT3 phosphorylation at tyrosine 705 residue effectively in a dose- and time-dependent manner. The phosphorylation of Janus-activated kinases (JAKs) 1 and 2 and Src was also suppressed by lupeol. Pervanadate treatment reversed the downregulation of phospho-STAT3 induced by lupeol, thereby indicating the involvement of a phosphatase. Indeed, we observed that treatment with lupeol increased the protein and mRNA levels of SHP-2, and silencing of SHP-2 abolished the inhibitory effects of lupeol on STAT3 activation. Treatment with lupeol also downregulated the expression of diverse STAT3-regulated genes and decreased the binding of STAT3 to VEGF promoter. Moreover, the proliferation of various HCC cells was significantly suppressed by lupeol, being associated with substantial induction of apoptosis. Depletion of SHP-2 reversed the observed antiproliferative and pro-apoptotic effects of lupeol. Conclusions: Lupeol exhibited its potential anticancer effects in HCC through the downregulation of STAT3-induced pro-survival signalling cascade.

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