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.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide due to the lack of effective therapy options
Tumor recurrence and metastasis are common in HCC1
Diol-type ginsenosides inhibit cancer cells proliferation We selected five kinds of monomers, namely, Rg5, Rh2, Rh3, Rg3, and PPD to verify the ability of diol-type ginsenosides in exhibiting inhibitory effects on cell viability (Fig. 1a)
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide due to the lack of effective therapy options. Rare ginsenosides extracted from ginseng have substantial biological activities, including immune regulatory, antioxidation, anti-inflammation, and antitumor effects[9,10]. These ginsenosides are mainly divided into diol- and trioltype ginsenosides. Official journal of the Cell Death Differentiation Association. Yang et al Cell Death and Disease (2019)10:630 compounds have been identified[11]. Diol-type ginsenosides mainly include Rb1, Rd, Rh2, Rg3, Rg5, and Rk112. Several studies reported the antitumor effects and mechanisms of different diol-type ginsenoside-related pathways, including ROS/JNK/p53, Wnt/β-catenin, and ERK. Reports on the antitumor effects of PPD and its molecular mechanisms are insufficient[13,14,15,16]
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