(20S) Ginsenoside Rh2 Inhibits STAT3/VEGF Signaling by Targeting Annexin A2

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.

Annexin A2: The diversity of pathological effects in tumorigenesis and immune response

“…55,56 A study in 2021 showed that using (20S) ginsenoside Rh2, a natural ginseng extract with anticancer activity, interfered with the interaction of ANXA2 and STAT3, and inhibited STAT3 phosphorylation, thereby inhibiting tumor development-related processes. 57 Furthermore, the phosphorylation of ANXA2 at Tyr-23 was confirmed to be necessary for ANXA2 monomer located on the cell membrane by using ANXA2 Tyr-23 mutant approach. 20 Tyrosine phosphorylation of ANXA2 is an important process in triggering Rho/Rho-associated coiled-coil-containing protein kinase(ROCK) pathway related to cell adhesion control.…”

“…As a result, E‐cadherin gene (CDH1) transcription was inhibited, and vimentin and MMP2/9 expression were upregulated, thereby promoting the pathological process of EMT 55,56 . A study in 2021 showed that using (20S) ginsenoside Rh2, a natural ginseng extract with anticancer activity, interfered with the interaction of ANXA2 and STAT3, and inhibited STAT3 phosphorylation, thereby inhibiting tumor development‐related processes 57 . Furthermore, the phosphorylation of ANXA2 at Tyr‐23 was confirmed to be necessary for ANXA2 monomer located on the cell membrane by using ANXA2 Tyr‐23 mutant approach 20 .…”

The role of IL-6/JAK2/STAT3 signaling pathway in cancers

“…Overactivation of STAT3 can promote tumor growth either directly through tumor autonomic mechanisms or indirectly by modulating antitumor responses of tumor-associated stroma and immune system. Constitutively activated STAT3 in tumor cells not only eliminates anti-tumor immune response by continuously promoting IL-6 (91), IL-10 (91) or vascular endothelial growth factor (VEGF) (92) in the TME, but also transcribes and activates key oncogenes involved in immunosuppression such as programmed cell death-ligand 1 (PD-L1) (93), indoleamine 2, 3-dioxygenase 1 (IDO1) (94). The high expression of STAT3 thus enhances immune escape ability or establishes immune tolerance through a variety of mechanisms, and the inflammatory microenvironment further promotes tumor angiogenesis and the growth, invasion and metastasis of tumor cells (95).…”

Research progress of ginseng in the treatment of gastrointestinal cancers

“…Common clinical precancerous lesions of the GI tract include: chronic atrophic gastritis and gastric ulcer (GU), chronic hepatitis and cirrhosis, colon and rectal polyps, and epithelial hyperplasia. ( Wang Y et al, 2021 ).…”