Abstract
Signal transducers and activators of transcription 3 (STAT3) acts as a transcriptional signal transducer, converting cytokine stimulation into specific gene expression. In tumor cells, aberrant activation of the tyrosine kinase pathway leads to excessive and continuous activation of STAT3, which provides further signals for tumor cell growth and surrounding angiogenesis. In this process, the tumor-associated protein Annexin A2 interacts with STAT3 and promotes Tyr705 phosphorylation and STAT3 transcriptional activation. In this study, we found that (20S) ginsenoside Rh2 (G-Rh2), a natural compound inhibitor of Annexin A2, inhibited STAT3 activity in HepG2 cells. (20S) G-Rh2 interfered with the interaction between Annexin A2 and STAT3, and inhibited Tyr705 phosphorylation and subsequent transcriptional activity. The inhibitory activity of STAT3 leaded to the negative regulation of the four VEGFs, which significantly reduced the enhanced growth and migration ability of HUVECs in co-culture system. In addition, (20S)G-Rh2 failed to inhibit STAT3 activity in cells overexpressing (20S)G-Rh2 binding-deficient Annexin A2-K301A mutant, further proving Annexin A2-mediated inhibition of STAT3 by (20S)G-Rh2. These results indicate that (20S)G-Rh2 is a potent inhibitor of STAT3, predicting the potential activity of (20S)G-Rh2 in targeted therapy applications.
Highlights
Signal transducers and activators of transcription 3 (STAT3), a member of signal transducers and activators of transcription (STATs) family, participates in various critical cellular processes including cell proliferation, survival, differentiation, and angiogenesis [1,2,3,4,5]
In order to expound the regulatory effect of Annexin A2 (Anxa2) on STAT3 activation, we lowered the expression of Anxa2 in HepG2 cells by Anxa2shRNA, and both Tyr705 phosphorylation and transcriptional activation of STAT3 were inhibited and accorded with the protein level of Anxa2 (Figure 1A,B)
In tumor cells and tumor microenvironment, excessive cytokines and functional mutation of kinase pathway members alter the regulation of tyrosine kinase pathway, providing a hyper-phosphorylation status at STAT3- Tyr705, which drives the head-to-tail dimerization and following activation [35,36]
Summary
STAT3, a member of signal transducers and activators of transcription (STATs) family, participates in various critical cellular processes including cell proliferation, survival, differentiation, and angiogenesis [1,2,3,4,5]. Cytokines activate receptor-linked tyrosine kinases like Src family members and JAKs, which phosphorylates STAT3 and induces the homologous dimerization and nucleus localization, STAT3 binds to DNA sequences of target genes including cyclins, anti-apoptosis proteins, vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs), and immuno-suppressive proteins [5,8,9]. STAT3 transforms to hyper- and sustainingactivated in cancer for the excessive cytokine supply and ultra-active mutation within kinase pathway, which promotes cancer metastasis, angiogenesis, and immuno-suppression. Aberrant STAT3 hyper-activation has been estimated to present in over 70% of human cancer and reported in almost all types of malignancies with a poor clinical outcome [5,12,13], and STAT3 together with its relative signaling pathway has long been recognized as a potential therapeutic target [1,5,7,9,12]
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