Protopanaxadiol inhibits epithelial–mesenchymal transition of hepatocellular carcinoma by targeting STAT3 pathway

Abstract

Diol-type ginsenosides, such as protopanaxadiol (PPD), exhibit antioxidation, anti-inflammation, and antitumor effects. However, the antitumor effect of these ginsenosides and the mechanism of PPD remain unclear. In this work, the antitumor effects of several derivatives, including PPD, Rg5, Rg3, Rh2, and Rh3, were evaluated in five different cancer cell lines. PPD demonstrated the best inhibitory effects on the proliferation and migration of the five cancer cell lines, especially the hepatocellular carcinoma (HCC) cell lines. Therefore, the mechanism of action of PPD in HCC cells was elucidated. PPD inhibited the proliferation, migration, and invasion ability of HepG2 and PLC/PRF/5 cells in a dose-dependent manner. Western blot and immunofluorescence assay showed that PPD can alter the expression of epithelial–mesenchymal transition markers, increase E-cadherin expression, and decrease vimentin expression. Docking and biacore experiments revealed that STAT3 is the target protein of PPD, which formed hydrogen bonds with Gly583/Leu608/Tyr674 at the SH2 domain of STAT3. PPD inhibited the phosphorylation of STAT3 and its translocation from the cytosol to the nucleus, thereby inhibiting the expression of Twist1. PPD also inhibited tumor volume and tumor lung metastasis in PLC/PRF/5 xenograft model. In conclusion, PPD can inhibit the proliferation and metastasis of HCC cells through the STAT3/Twist1 pathway.

JAK/STAT signaling in hepatocellular carcinoma

“…Besides, STAT3 can also induce the invasiveness of HCC tumors by upregulating the expression of epithelial-mesenchymal transition proteins such as Slug and Twist [61,62]. In fact, targeting STAT3 led to a reduction in these proteins, while simultaneously increasing the expression of adhesion protein, E-cadherin, to reduce the metastatic potential of the cells both in vitro and in vivo [63].…”

Anti-Angiogenic Properties of Ginsenoside Rg3

“…From this perspective Rg3 might not be the best candidate for oral administration. It is rapidly metabolized in the gastrointestinal tract (GIT), going through partial or complete hydrolysis in the stomach and losing the sugar moieties by the GIT anaerobic microflora, leaving de-glycosylated active anti-cancer metabolites such as ginsenoside Rh2 and protopanaxadiol (PPD) [ 100 , 101 , 102 ]. Rg3 is also a substrate for cytochrome P450 members, which are abundant in the liver and GIT and also found in other organs including skin, blood, lungs and kidneys.…”

Identification of potential diagnostic biomarkers in MMPs for pancreatic carcinoma

“…Overexpression of ETV4 promotes progression, proliferation and invasion of many carcinomas. [ 43 , 69 , 70 ] STAT3 regulates glycolysis in hepatocellular carcinoma cells, [ 71 ] is associated with inhibition of epithelial-mesenchymal transition inhepatocellular carcinoma, [ 72 ] and is related to proliferation promotion and apoptosis inhibition in esophageal squamous cell carcinoma. [ 73 , 74 ] Previous studies have also identified a role for STAT3 in the regulation of PC.…”