Ginsenoside Rb2 inhibits epithelial-mesenchymal transition of colorectal cancer cells by suppressing TGF-β/Smad signaling.

Treating colorectal cancer (CRC) continues to be a clinical challenge. Studies have shown that epithelial-mesenchymal transition (EMT) is a critical step in tumor progression and transforming growth factor-β1 (TGF-β1) signaling has been shown to play a crucial role in EMT. Here, we investigate the inhibition effect of Ginsenoside Rb2, main bioactive component of ginseng, in human colorectal cancer cells via TGF-β1. The current study aims to study the inhibitory effect of Ginsenoside Rb2 on HCT116 and SW620 cells and its anti-tumor mechanism. Histomorphological analysis and western blot analysis were performed to evaluate expression of TGF-β1 in human cancerous colon samples and the adjacent normal samples. The docking simulation assay were performed to explore the potential mode of binding of Ginsenoside Rb2 to the TGF-β1 protein. CCK8, adhesion and invasion assay were used to assess the effects of Ginsenoside Rb2 in HCT116 and SW620 cells. RT-PCR, Western blot and Immunohistochemical staining were employed to detect the TGF-β1-related signaling pathways in the colon cancer cells and/or xenograft mice. The expression of TGF-β1 in human cancerous colon samples was significantly increased compared with the adjacent normal samples. Ginsenoside Rb2 inhibit the growth, adhesion, EMT and metastasis of human colorectal cancer cells. The docking simulation assay confirmed that Ginsenoside Rb2 bound to the hydrophobic pocket of TGF-β1, which partially overlaps with the binding sites on TGF-β1, and thus disrupted TGF-β1 dimerization. Western Blot analysis further confirmed that Ginsenoside Rb2 could inhibit the expression of TGF-β1 in vitro and in vivo. Furthermore, Ginsenoside Rb2 could inhibit the expression of Smad4 and phosphorylated Smad2/3. Ginsenoside Rb2 could inhibit EMT of colorectal cancer cells through the TGF-β1/Smad signaling, and might be a potential candidate for the treatment of colorectal cancer.

Dai G ，Sun B ，Gong T ，Pan Z ，Meng Q ，Ju W ... -  《-》

Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression.

Ji Q ，Liu X ，Han Z ，Zhou L ，Sui H ，Yan L ，Jiang H ，Ren J ，Cai J ，Li Q ... -  《BMC CANCER》

The anti-metastatic effect of ginsenoside Rb2 in colorectal cancer in an EGFR/SOX2-dependent manner.

Ginsenoside Rb2, a saponin from Panax ginseng, has been shown to have many functions. However, the effect of ginsenoside Rb2 on the metastasis of colorectal cancer (CRC) remains unknown. CRC cell lines HT29 and SW620 were used to determine the effects of ginsenoside Rb2 on the colony-forming, migration, invasion, and wound-healing abilities of CRC cells in vitro. Further, ginsenoside Rb2 was given intraperitoneally at 5 mg/kg of mouse body weight to check its effect on the metastasis of CRC cells in vivo. Ginsenoside Rb2 decreased colony-forming ability, migration, invasion, and wound healing of CRC cells in vitro, although it did not affect cell proliferation. As a possible mechanism, we found that ginsenoside Rb2 down-regulated the expression of stemness and Epithelial-mesenchymal transition (EMT)-related genes via the EGFR/SOX2 signaling axis; these were partially rescued by either exogenous EGF treatment or ectopic expression of SOX2. More importantly, ginsenoside Rb2 significantly reduced the number of metastatic nodules in the livers, lungs, and kidneys in a mouse model of metastasis. These results suggest that ginsenoside Rb2 could be used to treat the metastasis of CRC therapeutically or as a supplement.

Phi LTH ，Wijaya YT ，Sari IN ，Yang YG ，Lee YK ，Kwon HY ... -  《Cancer Medicine》

Chinese medicine Bu-Fei decoction attenuates epithelial-mesenchymal transition of non-small cell lung cancer via inhibition of transforming growth factor β1 signaling pathway in vitro and in vivo.

Traditional Chinese medicine Bu-Fei decoction (BFD) has been utilized to treat patients with Qi deficiency for decades, with the advantages of invigorating vital energy, clearing heat-toxin and moistening lung, etc. According to previous clinical experience and trials, BFD has been found to indeed improve life quality of lung cancer patients and prolong survival time. Nevertheless, little is known on its potential mechanisms so far. Being regarded as a pivotal cytokine in the tumor microenvironment, transforming growth factor β (TGF-β) stands out as a robust regulator of epithelial-mesenchymal transition (EMT), which is closely linked to tumor progression. The present study was designed to explore whether BFD antagonized EMT via blocking TGF-β1-induced signaling pathway, and then help contribute to create a relatively steady microenvironment for confining lung cancer. This experiment was performed in lung adenocarcinoma A549 cells both in vitro and in vivo. In detail, the influences mediated by TGF-β1 alone or in combination with different concentrations of BFD on migration were detected by wound healing and transwell assays, and the effects of BFD on cell viability were determined by cell counting kit-8 (CCK-8) assay. TGF-β1, EMT relevant proteins and genes were evaluated by western blotting, confocal microscopy, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC) and enzyme-linked immuno sorbent assay (ELISA). Female BALB/C nude mice were subcutaneously implanted A549 cells and given BFD by gavage twice daily for 28 days. The tumor volume was monitored every 4 days to draw growth curve. The tumor weight, expression levels of EMT-related protein in tumor tissues and TGF-β1 serum level were evaluated, respectively. BFD only exerted minor effects on A549 cell proliferation and this was in accordance with the in vivo result, which showed that the tumor growth and weight were not be restrained by BFD administration. However, the data elucidated that BFD could dose-dependently suppress EMT induced by TGF-β1 in vitro via attenuating canonical Smad signaling pathway. In the A549 xenograft mouse model, BFD also inhibited protein markers that are associated with EMT and TGF-β1 secretion into serum. Based on these above data, the conclusion could be put forward that BFD probably attenuated TGF-β1 mediated EMT in A549 cells via decreasing canonical Smad signaling pathway both in vitro and in vivo, which may help restrain the malignant phenotype induced by TGF-β1 in A549 cells to some extent.

He XR ，Han SY ，Li XH ，Zheng WX ，Pang LN ，Jiang ST ，Li PP ... -  《-》

Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance.

The epithelial-mesenchymal transition (EMT) is a pivotal cellular process during which epithelial polarized cells become motile mesenchymal-appearing cells, which, in turn, promotes the metastatic potential of cancer. Ginseng is a perennial plant belonging to the genus Panax that exhibits a wide range of pharmacological and physiological activities. Ginsenosides 20-Rg3, which is the active component of ginseng, has various medical effects, such as anti-tumorigenic, anti-angiogenesis, and anti-fatiguing activities. In addition, ginsenosides 20(S)-Rg3 and 20(R)-Rg3 are epimers, and this epimerization is produced by steaming. However, the possible role of 20(S)-Rg3 and 20(R)-Rg3 in the EMT is unclear. We investigated the effect of 20(S)-Rg3 and 20(R)-Rg3 on the EMT. Transforming growth factor-beta 1 (TGF-β1) induces the EMT to promote lung adenocarcinoma migration, invasion, and anoikis resistance. To understand the repressive role of 20(S)-Rg3 and 20(R)-Rg3 in lung cancer migration, invasion, and anoikis resistance, we investigated the potential use of 20(S)-Rg3 and 20(R)-Rg3 as inhibitors of TGF-β1-induced EMT development in A549 lung cancer cells in vitro. Here, we show that 20(R)-Rg3, but not 20(S)-Rg3, markedly increased expression of the epithelial marker E-cadherin and repressed Snail upregulation and expression of the mesenchymal marker vimentin during initiation of the TGF-β1-induced EMT. 20(R)-Rg3 also inhibited the TGF-β1-induced increase in cell migration, invasion, and anoikis resistance of A549 lung cancer cells. Additionally, 20(R)-Rg3 markedly inhibited TGF-β1-regulated matrix metalloproteinase-2 and activation of Smad2 and p38 mitogen activated protein kinase. Taken together, our findings provide new evidence that 20(R)-Rg3 suppresses lung cancer migration, invasion, and anoikis resistance in vitro by inhibiting the TGF-β1-induced EMT.

Kim YJ ，Choi WI ，Jeon BN ，Choi KC ，Kim K ，Kim TJ ，Ham J ，Jang HJ ，Kang KS ，Ko H ... -  《-》