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.
Highlights
Ovarian cancer, existing predominantly in the form of epithelial ovarian cancer (EOC), is the most lethal gynecologic malignancy [1,2]
hypoxia-inducible factor-1 alpha (HIF-1a) is hydroxylated by a family of proline hydroxylases (PHD1-3) at Pro402 and Pro564, leading to a conformational change that promotes HIF-1a binding to the von Hippel Lindau protein (VHL) - a component of the large E3 ubiquitin ligase complex that mediates proteasomal degradation of HIF-1a [7,8]
The membranes were blocked with 5% non-fat milk at room temperature for 1 hour, probed overnight with primary antibody (E-cadherin 1:500, vimentin 1:2000, b-actin 1:1000, HIF-1a 1:500, PHD1 1:2000, VHL 1:1000) in TBST followed by incubation with appropriate horse radish peroxidase (HRP) conjugated secondary antibody
Summary
Ovarian cancer, existing predominantly in the form of epithelial ovarian cancer (EOC), is the most lethal gynecologic malignancy [1,2]. EMT suppresses epithelial cell-specific E-cadherin via action of various mediators, leading to the loss of apical-basal polarity and cell-cell adhesion junction, and up-regulates mesenchymal cell-specific vimentin [20] resulting in cytoskeleton rearrangement and cell motility enhancement. These events constitute the fundamental features of EMT at the molecular level. Stereoisomers 20(R)-Rg3 and 20(S)-Rg3 are two optically active chiral molecules differing in the orientation of the hydroxyl (OH) group on carbon-20 [24] Both have been reported to inhibit tumor metastasis [30], stereospecifity of Rg3 appears to be linked to their bioactivities. We have discovered for the first time that 20(S)-Rg3 effectively inhibits hypoxia-induced EMT of human ovarian cancer cells in vitro and in nude mouse xenograft models, promising a novel natural agent for antiovarian cancer therapy
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