Celastrol inhibits migration and invasion through blocking the NF-κB pathway in ovarian cancer cells

Abstract

Abstract. Metastatic ovarian cancer is a major clinical challenge with poor prognosis and high mortality. Celastrol is a natural compound that has exhibits antiproliferative activity; however, its effects on metastasis-related phenotypes in ovarian cancer models are unclear. In the current study, the anti-invasive activities and associated signaling pathways of celastrol were determined in ovarian cancer cells. Cell proliferation was tested by MTT assay. Cell migration was detected by wound healing and Transwell assays, while cell invasion was detected by a Matrigel-coated Transwell method. In addition, nuclear factor (NF)-κB and matrix metalloproteinase (MMP) expression was examined by western blotting, and MMP-2/-9 activities were determined by gelatin zymography. At sub-toxic concentrations (<0.5 µM), celastrol inhibited migration and invasion in a concentration-dependent manner in SKOV-3 and OVCAR-3 cells. At the molecular level, celastrol blocked the canonical NF-κB pathway by inhibiting IκBα phosphorylation, and preventing IκBα degradation and p65 accumulation. Furthermore, the expression and activity of the NF-κB target protein MMP-9, but not MMP-2, were inhibited by celastrol. Furthermore, celastrol showed no synergistic effect with MG132, an NF-κB inhibitor. In conclusion, celastrol exhibited significant anti-invasive activities in ovarian cancer cells. Such functions may be mediated via NF-κB pathway blockade. The results of this in vitro study strengthen the value of applying celastrol as a potential clinical intervention modality for delaying ovarian cancer metastasis. This, celastrol warrants further preclinical investigation.

Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells

“…In this study, we found that celastrol dramatically inhibited liver cancer cell migration in vitro which is likely the mechanism of action underlying celastrol-mediated inhibition of hepatocellular carcinoma invasiveness in vivo. According to previous studies, celastrol takes anti-metastasis effect via multiple targets, such as inhibiting PTEN/PI3K/AKT pathway 43 , NF-κB pathway 44 and HSP90-HIF1α-VEGF pathway 45 . Moreover, celastrol could also target tumor microenvironment, such as inhibiting IL-1β production 30 , suppressing M2-like polarization macrophages 42 , inhibiting angiogenesis 40 and reducing matrix metalloproteinase 46 .…”

A Tf-modified tripterine-loaded coix seed oil microemulsion enhances anti-cervical cancer treatment

“…According to previous reports, tripterine suppresses the proliferation of tumor cells via the mitochondrial apoptosis pathway. [11][12][13][14][15][16][17] However, whether mitochondrial-targeted delivery of tripterine could amplify the apoptotic effect is not yet known. As shown in Figure 2D, the mitochondria were stained with red fluorescence (MitoTracker Red) and the formulation was labeled with green fluorescence (FITC).…”

“…[8][9][10] The antitumor mechanisms of tripterine involve the upregulation of mitochondrial apoptotic proteins (Bcl-2 and Bax), interference with the expression of nuclear transcription factors (NF-κB), and blocking inflammatory pathways of NF-κB. [11][12][13][14][15][16][17] Owing to its potent antitumor and anti-inflammatory activities, tripterine is identified as one of the five most promising natural drugs of the 21st century. 18 Until now, however, no commercial preparation has been used in clinical application due to its poor water solubility and severe systemic toxicity, including sharp weight loss and acute liver damage.…”

Celastrol Inhibits Migration and Invasion of Triple-Negative Breast Cancer Cells by Suppressing Interleukin-6 via Downregulating Nuclear Factor-κB (NF-κB)

“…A growing number of studies have reported the anti-metastatic roles of celastrol in many cancers, including ovarian cancer, chondrosarcoma, and osteosarcoma [ 19 – 21 ]. Moreover, previous studies showed that celastrol repressed phorbol 12-myristate 13-acetate-induced migration and invasion of MCF-7 breast cancer cells at various concentrations (0.1–2.5 μM) [ 15 ].…”