title: Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009 Jiangsu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Xueting
authors.initials: X
authors.lastname: Cai
authors.forename: Wuguang
authors.initials: W
authors.lastname: Lu
authors.forename: Chunping
authors.initials: C
authors.lastname: Hu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D015850:Interleukin-6; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C049639:evodiamine; D053614:Janus Kinase 2; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6