Beta-Elemene Blocks Epithelial-Mesenchymal Transition in Human Breast Cancer Cell Line MCF-7 through Smad3-Mediated Down-Regulation of Nuclear Transcription Factors

Zhang, Xian; Li, Yinghua; Zhang, Yang; Song, Jing; Wang, Qimin; Zheng, Liqin; Liú, Dan

doi:10.1371/journal.pone.0058719

Cited by 49 publications

(36 citation statements)

References 50 publications

(45 reference statements)

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“…Many transcriptional repressors including Snail and Twist play important role in role in TGF-β1 induced EMT [30]. Further we assessed the levels of Snail and Twist in RT-PCR studies, which were significantly elevated after irradiation and this effect was reversed by halofuginone.…”

Section: Discussionmentioning

confidence: 99%

Halofuginone inhibits radiotherapy-induced epithelial-mesenchymal transition in lung cancer

et al. 2016

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Radiotherapy is used to treat many different human tumors. Paradoxically, radiation can activate TGF-β1 signaling and induce the epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor progression. This study investigated the inhibitory effects of halofuginone, a plant-derived alkaloid that has been shown to inhibit TGF-β1 signaling, on radiation-induced EMT and explored the underlying mechanisms using a Lewis lung carcinoma (LLC) xenograft model. The cells and animals were divided into five treatment groups: Normal Control (NC), Halofuginone alone (HF), Radiotherapy alone (RT), Radiotherapy combined with Halofuginone (RT+HF), and Radiotherapy combined with the TGF-β1 inhibitor SB431542 (RT+SB). Radiation induced EMT in lung cancer cells and xenografts, as evidenced by increased expression of the mesenchymal markers N-cadherin and Vimentin, and reduced expression of the epithelial markers E-cadherin and Cytokeratin. Further, radiotherapy treatment increased the migration and invasion of LLC cells. Halofuginone reversed the EMT induced by radiotherapy in vitro and in vivo, and inhibited the migration and invasion of LLC cells. In addition, TGF-β1/Smad signaling was activated by radiotherapy and the mRNA expression of Twist and Snail was elevated; this effect was reversed by halofuginone or the TGF-β1 inhibitor SB431542. Our results demonstrate that halofuginone inhibits radiation-induced EMT, and suggest that suppression of TGF-β1 signaling may be responsible for this effect.

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Section: Discussionmentioning

confidence: 99%

Halofuginone inhibits radiotherapy-induced epithelial-mesenchymal transition in lung cancer

et al. 2016

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“…TGF‐β is an important inducer of EMT in cancer progression. Many papers have reported that TGF‐β could induce EMT in the MCF‐7 cells (Zhang et al, ; Walsh and Damjanovski, ). In our experiment, MCF‐7 cells were treated with TGF‐β1 at different concentrations (0, 5, or 10 ng/ml) for 48 h followed by Western blot analysis for different mesenchymal markers.…”

Section: Resultsmentioning

confidence: 99%

Epithelial‐to‐Mesenchymal Transition Induced by TGF‐β1 Is Mediated by AP1‐Dependent EpCAM Expression in MCF‐7 Cells

Gao

Qiu

Wang

et al. 2014

Journal Cellular Physiology

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The epithelial-to-mesenchymal transition (EMT), a process involving the breakdown of cell-cell junctions and loss of epithelial polarity, is closely related to cancer metastasis and invasion. The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane protein expressed in the majority of normal epithelial tissues and overexpressed in the majority of human epithelial cancers including breast cancer. EpCAM plays an important role in cancer progression. We showed that EpCAM participated in TGF-β1-induced EMT. TGF-β1 treatment of MCF-7 breast cancer cells was shown to induce EpCAM expression, which promoted the EMT and cell migration. EpCAM overexpression further enhanced TGF-β1-induced EMT and EpCAM knockdown inhibited TGF-β1-induced EMT. We further demonstrated that TGF-β1 treatment induced the phosphorylation of JNK that was in turn responsible for the increased expression of Jun and Fos. This result suggests an important role of the JNK to AP-1 signaling to EpCAM downstream of TGF-β1 for the induction of EMT in the breast cancer cells. Collectively, our study highlights a novel function for EpCAM in TGF-β1-induced EMT process and suggests that targeting of EpCAM may be an attractive strategy to treat breast cancer. This study implicates the potential value of EpCAM as a molecular marker for breast cancer.

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“…We previously showed that β-elemene significantly suppresses breast cancer cells growth and proliferation [15,16], β-elemene has a wide range of applications in traditional medicine, it has been studied as an agent capable of reversing resistance to chemotherapy [17,18]. Previous Chinese publication has shown that by up-regulating the expression of c-Cbl and Cbl-b, which leads to inhibition of PI3K/Akt signaling and down-regulation of Pgp expression [19].…”

Section: Discussionmentioning

confidence: 99%

�-Elemene Reverses Chemoresistance of Breast Cancer via Regulating MDR-Related MicroRNA Expression

Zhang

Chen

et al. 2014

Cell Physiol Biochem

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Background: Multidrug resistance (MDR) directly contributes to the clinical failure of chemotherapy in breast cancer (BCA). β-elemene is a natural antitumor drug from plants. We previously confirmed that MDR could be reversed by β-elemene. In this study, we intended to investigate the reversal effect of β-elemene on MDR in human BCA adriacin (Adr) -resistant MCF-7 cells (MCF-7/Adr) and docetaxel (Doc) - resistant MCF-7 cells (MCF-7/Doc) through the gene regulatory network. Methods: MTT-cytotoxic, miRNA microarray, Real-time quantitative PCR, Dual Luciferase Activity Assay, Western blot analysis were performed to investigate the impact of β-elemene on chemo-resistant BCA cell suvival, and its impact on the expression of chemo-resistance specific miRNA and the downstream target genes PTEN and Pgp. Results: Compared with the miRNAs expression profiles of MCF-7/Adr and MCF-7/Doc cell lines from our previous studies, there were 322 differentially expressed miRNAs in MCF-7/Adr and MCF-7/Doc breast cancer cells with β-elemene intervention (50μM/L) for 30h, and 6 miRNAs were significantly up-regulated and 12 miRNAs were significantly down-regulated in both MCF-7/Adr and MCF-7/Doc. We have testified that 5 miRNA is related to MDR before, in this study, the expression of miR-34a, miR-222, miR-452 and miR-29a can lead to changes of the characteristics of chemo-resistant MCF-7/Adr and MCF-7/Doc. The PTEN expression under intervention of β-elemene was significantly increased and Pgp expression under β-elemene intervention was significantly decreased in both cell lines. Conclusions: β-elemene could influence MDR related miRNA expression and subsequently regulate the expression of the target genes PTEN and Pgp, which may lead to reduction of the viability of the chemo-resistant breast cancer cells.

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Beta-Elemene Blocks Epithelial-Mesenchymal Transition in Human Breast Cancer Cell Line MCF-7 through Smad3-Mediated Down-Regulation of Nuclear Transcription Factors

Cited by 49 publications

References 50 publications

Halofuginone inhibits radiotherapy-induced epithelial-mesenchymal transition in lung cancer

Halofuginone inhibits radiotherapy-induced epithelial-mesenchymal transition in lung cancer

Epithelial‐to‐Mesenchymal Transition Induced by TGF‐β1 Is Mediated by AP1‐Dependent EpCAM Expression in MCF‐7 Cells

�-Elemene Reverses Chemoresistance of Breast Cancer via Regulating MDR-Related MicroRNA Expression

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