Abstract
The activation of signal transducer and activator of transcription 3 (STAT3) has been linked with the proliferation, survival, invasion, and angiogenesis of a variety of human cancer cells, including hepatocellular carcinoma (HCC). Agents that can suppress STAT3 activation have potential for the prevention and treatment of HCC. In this study, we tested an agent, β-escin, for its ability to suppress STAT3 activation. We found that β-escin, a pentacyclic triterpenoid, inhibited both constitutive and interleukin-6-inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed the β-escin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that β-escin induced the expression of tyrosine phosphatase Src homology phosphatase 1 that correlated with the down-regulation of constitutive STAT3 activation. β-Escin also down-regulated the expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, and vascular endothelial growth factor. Finally, β-escin inhibited proliferation and also substantially potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, these results suggest that β-escin is a novel blocker of STAT3 activation that may have potential in the suppression of proliferation and chemosensitization in HCC.
Footnotes
This work was supported by the Department of Research and Technology, National University of Singapore [Grant R-184-000-161-112] and the National Medical Research Council of Singapore [Grant R-184-000-168-275] (to G.S.). A.P.K. was supported by the National Medical Research Council of Singapore [Grant R-364-000-085-275] and the Cancer Science Institute of Singapore, Experimental Therapeutics I Program [Grant R-713-001-011-271]. K.M.H. was supported by the National Medical Research Council of Singapore [Grant NMRC/IBG/NCC/2009].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.165498.
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ABBREVIATIONS:
- STAT3
- signal transducer and activator of transcription 3
- HCC
- hepatocellular carcinoma
- FBS
- fetal bovine serum
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide
- JAK
- Janus-activated kinase
- PAGE
- polyacrylamide gel electrophoresis
- EGF
- epidermal growth factor
- VEGF
- vascular endothelial growth factor
- SHP1
- Src homology phosphatase 1
- PARP
- poly(ADP-ribose) polymerase
- PTP
- protein tyrosine phosphatase
- IL
- interleukin
- DMEM
- Dulbecco's modified Eagle's medium
- HRP
- horseradish peroxidase
- zVAD-FMK
- benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone
- AG490
- (E)-2-cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide
- NF-κB
- nuclear factor-κB.
- Received January 5, 2010.
- Accepted April 7, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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