Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells.
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, beta-escin, for its ability to suppress STAT3 activation. We found that beta-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 beta-escin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that beta-escin induced the expression of tyrosine phosphatase Src homology phosphatase 1 that correlated with the down-regulation of constitutive STAT3 activation. beta-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, beta-escin inhibited proliferation and also substantially potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, these results suggest that beta-escin is a novel blocker of STAT3 activation that may have potential in the suppression of proliferation and chemosensitization in HCC.
Tan
Sandra Min-Li
SM
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Li
Feng
F
Rajendran
Peramaiyan
P
Kumar
Alan Prem
AP
Hui
Kam M
KM
Sethi
Gautam
G
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004928:Escin / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008113:Liver Neoplasms; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
D000972:Antineoplastic Agents, Phytogenic; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004928:Escin; C507924:JAK2 protein, human; D053614:Janus Kinase 2