Inhibiting of self-renewal, migration and invasion of ovarian cancer stem cells by blocking TGF-β pathway

Abstract

Objective To investigate the effect and mechanism of SB525334 on self-renewal, migration and invasion of ovarian cancer stem cells. Methods ALDHhigh-expressing cancer stem cells (CSCs) were isolated from human ovarian cancer cell line SKOV-3 by flow cytometry and treated with 2μg/mL SB525334 for 6h. The sphere forming assay was used to detect the ability of self-renewal of CSCs and the colony formation assay was used to detect the tumorigenicity in vitro. Transwell migration and invasion assay were used to detect the migration and invasion ability of CSCs. To further explore the mechanism, real-time quantitative PCR and flow cytometry were used to detect the mRNA and protein expression of TGF-β, Smad2, Smad3, phosphorylated Smad2, phosphorylated Smad3 and Smad4, respectively. Expressions of epithelial-mesenchymal transition (EMT)related genes E-cadherin, Snail, Vimentin were also assessed. Results The self-renewal ability, tumorigenicity in vitro, migration and invasion ability of CSCs were significantly attenuated after SB525334 treatment. The expressions of TGF-β, phosphorylated Smad2, phosphorylated Smad3, Snail, and Vimentin were decreased, while Smad4 and E-cadherin expressions were increased. Conclusion SB525334 may inhibit the self-renewal, invasion and migration of ovarian CSCs by blocking the TGF-β/Smad/EMT pathway.

Role of exosomes in the immune microenvironment of ovarian cancer (Review)

“…The high expression of TGF-β3 is associated with poor prognosis of high-grade serous carcinoma, and it is a potential indicator for the evaluation of ovarian cancer prognosis (57). Recent studies have reported that in ovarian cancer stem cells, inhibition of TGF-β/SMAD pathway activation can further inhibit EMT (58)(59)(60). In 2012, Kulbe et al (61) first described the 'TNF' network in the ovarian cancer microenvironment.…”

TGF-β1 Receptor Inhibitor SB525334 Attenuates the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells via the TGF-β1 Signaling Pathway

“…Huang et al used a precision-cut liver tissue slice model that included all major cell types of liver parenchyma and showed anti-fibrotic effects of SB525334 in liver cells after bile duct ligation [27]. Other studies evaluated the influence of SB525334 on cancer models and revealed its inhibitory effects on the migration, invasion and EMT of cancer cells in the esophagus, liver, ovary and pancreas [8][9][10][11]. Furthermore, SB525334 attenuates the collagen production by reducing NADPH oxidase 4 in myoblasts [28].…”

“…Consequently, the transcription of the TGF-β-target genes, such as Snail, is initiated, which, in turn, triggers EMT. SB525334 is a potent TβRI inhibitor; previous studies have demonstrated that SB525334 blocks TGF-β-induced Smad activation and decreases EMT in some tissues/cell lines [8][9][10][11]. Considering the association between TGF-β signaling and EMT in peritoneal mesothelial cells, SB525334 may attenuate TGF-β signaling, resulting in a decrease in EMT and peritoneal membrane fibrosis.…”

Jorunnamycin A Suppresses Stem-Like Phenotypes and Sensitizes Cisplatin-Induced Apoptosis in Cancer Stem-Like Cell-Enriched Spheroids of Human Lung Cancer Cells

“…To determine the inhibitory effect on self-renewal [ 84 ], a single secondary CSC-enriched spheroid was isolated and treated with jorunnamycin A (0–0.5 µM). The alteration of spheroids after 0–7 days of jorunnamycin A treatment was observed under an inverted microscope (Nikon Ts2, Nikon, Japan) and presented as a relative value to spheroid size at day 0.…”