RT Journal Article
SR Electronic
T1 Identification of β-escin as a novel inhibitor of STAT3/JAK2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.110.165498
DO 10.1124/jpet.110.165498
A1 Sandra Min-Li Tan
A1 Feng Li
A1 Permaiyan Rajendran
A1 Alan Prem Kumar
A1 Kam Man Hui
A1 Gautam Sethi
YR 2010
UL http://jpet.aspetjournals.org/content/early/2010/04/09/jpet.110.165498.abstract
AB The activation of signal transducers and activators 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 prevention and treatment of HCC. In the present report, 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 SHP1 that correlated with down-regulation of constitutive STAT3 activation. β-escin also downregulated 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 b-escin is a novel blocker of STAT3 activation that may have a potential in suppression of proliferation and chemosensitization in HCC.The American Society for Pharmacology and Experimental Therapeutics