The activation of signal transducer and activator of transcription signaling 3 (STAT3) has been linked with the survival, proliferation, angiogenesis and immunosuppression of
hepatocellular carcinoma cells (HCCs). Agents that can suppress STAT3 activation have potential to be
cancer therapeutics. In this study, we investigated the inhibitory effect of
evodiamine on STAT3 pathway in vitro and the anti-
tumor effect of
evodiamine in vivo in HCC. We found that
evodiamine suppressed both constitutive and
interleukin-6 (IL-6)-induced activation of STAT3
tyrosine 705 (Tyr(705)) effectively. The phosphorylation of Janus-activated
kinase 2 (JAK2), Src and extracellular regulated
protein kinases 1/2 (ERK1/2) were also suppressed by
evodiamine. Interestingly, treatment of cells with
sodium pervanadate abrogated the inhibition of
evodiamine on IL-6-induced STAT3 (Tyr(705)) activation indicating the involvement of
protein tyrosine phosphatases. Indeed, further studies demonstrated that
evodiamine induced the expression of
phosphatase shatterproof 1 (SHP-1). Moreover, inhibition of SHP-1 gene by small interference RNA abolished the ability of
evodiamine to inhibit IL-6-induced STAT3 (Tyr(705)) activation.
Evodiamine also suppressed STAT3
DNA binding activity and down-regulated the expression of STAT3-mediated genes leading to the suppression of proliferation, induction of cell apoptosis and cell cycle arrest. In vivo,
evodiamine significantly inhibited
tumor growth in a subcutaneous xenograft model with HepG2 cells. In summary,
evodiamine blocked STAT3 signaling pathway by inducing SHP-1 and exhibited anticancer effect in vitro and in vivo.