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Br J Cancer. 2014 Sep 23;111(7):1327-37. doi: 10.1038/bjc.2014.422. Epub 2014 Aug 7.

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

Author information

1
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
2
Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
3
1] Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore [2] Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
4
1] Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore [2] Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore [3] Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6009, Australia [4] Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA.
5
1] Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore [2] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
6
Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore, Singapore.

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.

PMID:
25101566
PMCID:
PMC4183851
DOI:
10.1038/bjc.2014.422
[Indexed for MEDLINE]
Free PMC Article

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