Ginsenoside 20(S)-Rg3 Targets HIF-1α to Block Hypoxia-Induced Epithelial-Mesenchymal Transition in Ovarian Cancer Cells

Abstract

The prognosis of patients with ovarian cancer has remained poor mainly because of aggressive cancer progression. Since epithelial-mesenchymal transition (EMT) is an important mechanism mediating invasion and metastasis of cancer cells, targeting the EMT process with more efficacious and less toxic compounds to inhibit metastasis is of great therapeutic value for the treatment of ovarian cancer. We have found for the first time that the ginsenoside 20(S)-Rg3, a pharmacologically active component of the traditional Chinese herb Panax ginseng, potently blocks hypoxia-induced EMT of ovarian cancer cells in vitro and in vivo. Mechanistic studies confirm the mode of action of 20(S)-Rg3, which reduces the expression of hypoxia-inducible factor 1α (HIF-1α) by activating the ubiquitin-proteasome pathway to promote HIF-1α degradation. A decrease in HIF-1α in turn leads to up-regulation, via transcriptional suppression of Snail, of the epithelial cell-specific marker E-cadherin and down-regulation of the mesenchymal cell-specific marker vimentin under hypoxic conditions. Importantly, 20(S)-Rg3 effectively inhibits EMT in nude mouse xenograft models of ovarian cancer, promising a novel therapeutic agent for anticancer therapy.

Human endometrial mesenchymal stem cells exhibit intrinsic anti-tumor properties on human epithelial ovarian cancer cells

“…Animals were sacrificed by cervical dislocation under anesthetic status after 28 days. Tumor volume was calculated using the formula: tumor volume (mm 3 ) = 0.52 × (width [mm 2 ]) × (length [mm])58. To localize the EnSCs in the tumor microenvironment, we transfected EnSCs with GFP by lentivirus which was kindly provided by the Prof. Lijian Hui (Chinese Academic of Sciences, Shanghai, China).…”

Cellular stress response mechanisms as therapeutic targets of ginsenosides

“…HIF‐1α is regulated by ginsenosides through several mechanisms (Fig. ), including (1) the upregulation of HIF‐1α by Rb1 was completely abolished by 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole (YC‐1), which was shown to block the de novo synthesis of HIF‐1α through the inactivation of PI3K/Akt/mTOR pathway, accelerate the degradation of HIF‐1α, or block murine double minute 2 (Mdm2); (2) the Rg3‐mediated downregulation of HIF‐1α was reversed by inhibiting the phosphorylation of Akt and ERK1/2; and (3) HIF‐1α degradation was enhanced by Rg3 by activating the ubiquitin–proteasome pathway in a proline hydroxylase 1 (PHD1)‐von Hippel‐Lindau protein (VHL) dependent manner …”

In vitro inhibitory activities of six gypenosides on human liver cancer cell line HepG2 and possible role of HIF-1α pathway in them

“…Rg3 was used as a positive control, which a bioactive constituent of P. ginseng, has antitumor activity and is known to inhibit HIF-1a pathway [27].…”