Triptolide downregulates human GD3 synthase (hST8Sia I) gene expression in SK-MEL-2 human melanoma cells

Kwon, Haw Young; Kim, Seok Jo; Kim, Cheorl Ho; Son, Sung Wook; Kim, Kyoung Sook; Lee, Jai Heon; Il, Su; Lee, Young Choon

doi:10.3858/emm.2010.42.12.088

Cited by 29 publications

(43 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For this, we injected 0.5 × 10 6 RFP/luciferase-labeled MDA-MB-231 cells via the tail vein and subsequently treated the mice with either vehicle or triptolide for six weeks and analyzed for the presence of lung metastases using bioluminescent imaging. (24, 35) Whereas mice harboring vehicle-treated or control shRNA expressing MDA-MB-231 cells developed metastases (Figures 3d, e), inhibition of GD3S using triptolide or shRNA significantly reduced the metastatic burden (Figures 3d, e). …”

Section: Resultsmentioning

confidence: 96%

“…Likewise, the inhibition of GD3S activity in the aforementioned cells using the small molecule inhibitor triptolide(35) induced an epithelial-like morphology (Figure 1c) accompanied by a reduction in the expression of mesenchymal markers (Supplementary Figure 1a) without changing the rate of cell proliferation (Supplementary Figure 1b). In addition, we observed increased expression of the epithelial marker E-cadherin in HMLE-Snail, HMLE-Twist, and MDA-MB-231 cells, but not in SUM159 cells (Figure 1b and Supplementary Figure 1a).…”

Section: Resultsmentioning

confidence: 97%

See 1 more Smart Citation

GD3 synthase regulates epithelial–mesenchymal transition and metastasis in breast cancer

et al. 2014

View full text Add to dashboard Cite

The epithelial-mesenchymal transition (EMT) bestows cancer cells with increased stem cell properties and metastatic potential. To date, multiple extracellular stimuli and transcription factors have been shown to regulate EMT. Many of them are not druggable and therefore it is necessary to identify targets, which can be inhibited using small molecules to prevent metastasis. Recently, we identified the ganglioside GD2 as a novel breast cancer stem cell marker. Moreover, we found that GD3 synthase (GD3S)—an enzyme involved in GD2 biosynthesis—is critical for GD2 production and could serve as a potential druggable target for inhibiting tumor initiation and metastasis. Indeed, there is a small-molecule known as triptolide that has been shown to inhibit GD3S function. Accordingly, in this manuscript, we demonstrate that the inhibition of GD3S using shRNA or triptolide compromises the initiation and maintenance of EMT instigated by various signaling pathways, including Snail, Twist and TGF-β1 as well as the mesenchymal characteristics of claudin-low breast cancer cell lines (SUM159 and MDA-MB-231). Moreover, GD3S is necessary for wound healing, migration, invasion and stem cell properties in vitro. Most importantly, inhibition of GD3S in vivo prevents metastasis in experimental as well as in spontaneous syngeneic wild-type mouse models. We also demonstrate that the transcription factor FOXC2, a central downstream mediator/effector of several EMT pathways, directly regulates GD3S expression by binding to its promoter. In clinical specimens, the expression of GD3S correlates with poor prognosis in triple negative human breast tumors. Moreover, GD3S expression correlates with activation of the c-Met signaling pathway leading to increased stem cell properties and metastatic competence. Collectively, these findings suggest that the GD3S-c-Met axis could serve as an effective target for the treatment of metastatic breast cancers.

show abstract

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 97%

GD3 synthase regulates epithelial–mesenchymal transition and metastasis in breast cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Triptolide, a small molecule anti-inflammatory drug, has been shown to inhibit GD3S in a melanoma cancer cell line (25). Therefore, we investigated whether triptolide could inhibit GD3S in breast cancer cell lines as well.…”

Section: Hmler Cells Following Induction Of Emt By 25-fold In Snail mentioning

confidence: 99%

Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis

et al. 2012

View full text Add to dashboard Cite

“…Triptolide have been shown to inhibit experimental metastasis of B16F10 cells to the lungs and spleens of mice (Yang et al, ). Triptolide induces downregulation of hST8Sia I gene expression through NF‐κB activation in human melanoma cells (Kwon et al, ).…”

Section: Introductionmentioning

confidence: 99%

Suppression of the migration and invasion is mediated by triptolide in B16F10 mouse melanoma cells through the NF-kappaB-dependent pathway

Jao

et al. 2015

Environ. Toxicol.

View full text Add to dashboard Cite

Melanoma cancer is one of the major causes of death in humans worldwide. Triptolide is one of the active components of Tripterygium wilfordii Hook F, and has biological activities including induced cell cycle arrest and induction of apoptosis but its antimetastatic effects on murine melanoma cells have not yet been elucidated. Herein, we investigated the effect of triptolide on the inhibition of migration and invasion and possible associated signal pathways in B16F10 murine melanoma cancer cells. Wound healing assay and Matrigel Cell Migration Assay and Invasion System demonstrated that triptolide marked inhibiting the migration and invasion of B16F10 cells. Gelatin zymography assay demonstrated that triptolide significantly inhibited the activities of matrix metalloproteinases-2 (MMP-2). Western blotting showed that triptolide markedly reduced CXCR4, SOS1, GRB2, p-ERK, FAK, p-AKT, Rho A, p-JNK, NF-κB, MMP-9, and MMP-2 but increased PI3K and p-p38 and COX2 after compared to the untreated (control) cells. Real time PCR indicated that triptolide inhibited the gene expression of MMP-2, FAK, ROCK-1, and NF-κB but did not significantly affect TIMP-1 and -2 gene expression in B16F10 cells in vitro. EMSA assay also showed that triptolide inhibited NF-κB DNA binding in a dose-dependent manner. Confocal laser microscopy examination also confirmed that triptolide inhibited the expression of NF-κB in B16F10 cells. Taken together, we suggest that triptolide inhibited B16F10 cell migration and invasion via the inhibition of NF-κB expression then led to suppress MMP-2 and -9 expressions. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1974-1984, 2016.

show abstract

Triptolide downregulates human GD3 synthase (hST8Sia I) gene expression in SK-MEL-2 human melanoma cells

Cited by 29 publications

References 36 publications

GD3 synthase regulates epithelial–mesenchymal transition and metastasis in breast cancer

GD3 synthase regulates epithelial–mesenchymal transition and metastasis in breast cancer

Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis

Suppression of the migration and invasion is mediated by triptolide in B16F10 mouse melanoma cells through the NF-kappaB-dependent pathway

Contact Info

Product

Resources

About