Dioscin suppresses TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration and invasion

doi:10.1016/j.bmcl.2017.06.014

Bioorganic & Medicinal Chemistry Letters

Volume 27, Issue 15, 1 August 2017, Pages 3342-3348

https://doi.org/10.1016/j.bmcl.2017.06.014 Get rights and content

Abstract

Epithelial-to-mesenchymal transition (EMT), an important cellular process, occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Dioscin is a polyphenolic component isolated from Phyllanthus amarus, which exhibits a wide range of pharmacological and physiological activities, such as anti-tumor, anti-inflammatory, anti-obesity, anti-fungal, and anti-viral activities. However, the possible role of dioscin in the EMT is unclear. We investigated the suppressive effect of dioscin on the EMT. Transforming growth factor-beta 1 (TGF-β1) is known to induce EMT in a number of cancer cell types and promote lung adenocarcinoma migration and invasion. To verify the inhibitory role of dioscin in lung cancer migration and invasion, we investigated the use of dioscin as inhibitors of TGF-β1-induced EMT in A549 lung cancer cells in vitro. Here, we found that dioscin prominently increased expression of the epithelial marker E-cadherin and expression of the mesenchymal marker N-cadherin and Snail during the TGF-β1-induced EMT. In addition, dioscin inhibited the TGF-β1-induced increase in cell migration and invasion of A549 lung cancer cells. Also, dioscin remarkably inhibited TGF-β1-regulated activation of MMP-2/9, Smad2, and p38. Taken together, our findings provide new evidence that dioscin suppresses lung cancer migration, and invasion in vitro by inhibiting the TGF-β1-induced EMT.

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Conflict of interest

All the authors confirm that there is no potential conflict of interest regarding this publication.

Acknowledgements

This work was supported by Basic Science Research Programs through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF-2015R1D1A3A01017660 and NRF-2016R1A6A3A11935338).

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One of the most important and effective components of Astragalus membranaceus is astragaloside IV (AS-IV), which can exert anti-tumor effects through various pathways. For instance, AS-IV exerts an anti-tumor effect by acting at the cellular level, regulating the phenotype switch of tumor-associated macrophages, or inhibiting the development of tumor cells. Furthermore, AS-IV inhibits tumor cell progression by enhancing its sensitivity to antitumor drugs or reversing the drug resistance of tumor cells. This article reviews the different mechanisms of AS-IV inhibition of epithelial–mesenchymal transition (EMT), migration, proliferation, and invasion of tumor cells, inducing apoptosis and improving the sensitivity of anti-tumor drugs. This review summarizes recent progress in the current research into AS-IV anti-tumor effect and provides insight on the next anti-tumor research of AS-IV.
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Dioscin as the major steroidal saponin in Dioscorea nipponica Makino has been progressively reported for its antitumor effect against various cancers. In human lung cancer cells, dioscin could prevent proliferation, invasion and EMT probably by the inactivation of AKT/mTOR/GSK3β signaling pathway except for TGF-β1, and it could also induce autophagy-related cell apoptosis via modulation of PI3K/Akt and ERK and JNK signaling pathways (Mao et al., 2020; Lim et al., 2017; Hsieh et al., 2013). Cui et al. additionally reported that dioscin-mediated macrophage polarization might inhibit the in vivo metastasis of lung cancer cells via JNK and STAT3 pathways (Cui et al., 2020).
Dioscorea nipponica Makino as a Chinese folk medicine has been used for the treatment of chronic bronchitis, cough, and asthma. Several studies have established the antimetastatic potential of Dioscorea nipponica Makino extract. Dioscin is a major bioactive compound in Dioscorea nipponica Makino and has anti-tumor property in lung cancer cell lines. However, the preventive effect of dioscin against lung cancer and its key mechanism haven't been identified yet.
To identify the prevention effect of dioscin on lung cancer and explore its key mechanism based on network pharmacology and experimental validation.
The potential targets of dioscin were obtained from the HERB database. The therapeutic targets of lung cancer were acquired from the GeneCards database. Protein-protein interaction network (PPI) was constructed in the STRING 11.0 database. The David database was used for enrichment analysis. Molecular Docking was finished by the AutoDock Vina. NSCLC cell lines and mouse lung cancer model were used to confirm the prevention effect of dioscin on lung cancer and its key mechanism.
76 potential targets of dioscin were identified to be involved in lung cancer treatment, which refer to 512 biological processes, 47 molecular functions, 77 cellular components and 107 signal pathways. The molecular docking suggested that dioscin might bind to AKT1, Caspase3, TP53, C-JUN and IL-6. The DARTS indicated that dioscin could bind to AKT1. In vitro, dioscin could decrease proliferation, invasion and migration in A549 and PC-9 cells with the significant reduction in the expression of p-AKT, MMP2, and PCNA. In vivo, dioscin could reduce lung nodules, lung injury, and mortality in mouse lung cancer model with reducing the expression of p-AKT, MMP2, PCNA and increasing the expression of active-caspase3.
Dioscin could prevent lung cancer and its key target is AKT1 kinase, a center protein of PI3K/AKT signaling pathway.
Dioscin and diosgenin: Insights into their potential protective effects in cardiac diseases
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In addition, modern pharmacological research shows that in areas other than heart disease, dioscin and diosgenin have the potential to treat diabetes (Li, H. et al., 2019; Oyelaja-Akinsipo et al., 2020), osteoporosis (Tao et al., 2016; Zhang et al., 2018), inhibit fibrosis of the liver and kidney (Li et al., 2017; Qiao et al., 2018; Xie et al., 2015), we also found that dioscin has a good therapeutic effect on I/R injury of many organs (Hu et al., 2016, 2018; Qi et al., 2015; Tao et al., 2014). Moreover, dioscin and diosgenin have broad-spectrum antitumor effects, such as prostate cancer (Tao et al., 2017), lung cancer (Lim et al., 2017), liver cancer (Chen, Z. et al., 2018). Dioscin is a poorly soluble drug and is mainly administered orally in clinical practice.
Dioscin and diosgenin derived from plants of the genus Dioscoreaceae such as D. nipponica and D. panthaica Prain et Burk. Were utilized as the main active ingredients of traditional herbal medicinal products for coronary heart disease in the former Soviet Union and China since 1960s. A growing number of research showed that dioscin and diosgenin have a wide range of pharmacological activities in heart diseases.
To summarize the evidence of the effectiveness of dioscin and diosgenin in cardiac diseases, and to provide a basis and reference for future research into their clinical applications and drug development in the field of cardiac disease.
Literatures in this review were searched in PubMed, ScienceDirect, Google Scholar, China National Knowledge Infrastructure (CNKI) and Web of Science. All eligible studies are analyzed and summarized in this review.
The pharmacological activities and therapeutic potentials of dioscin and diosgenin in cardiac diseases are similar, can effectively improve hypertrophic cardiomyopathy, arrhythmia, myocardial I/R injury and cardiotoxicity caused by doxorubicin. But the bioavailability of dioscin and diosgenin may be too low as a result of poor absorption and slow metabolism, which hinders their development and utilization.
Dioscin and diosgenin need further in-depth experimental research, clinical transformation and structural modification or research of new preparations before they can be expected to be developed into new therapeutic drugs in the field of cardiac disease.
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Cancer is one of the major global health problems, responsible for the second-highest number of deaths. The genetic and epigenetic changes in the oncogenes or tumor suppressor genes alter the regulatory pathways leading to its onset and progression. Conventional methods are used in appropriate combinations for the treatment. Surgery effectively treats localized tumors; however, it fails to treat metastatic tumors, leading to a spread in other organs, causing a high recurrence rate and death. Among the different strategies, the nanocarriers-based approach is highly sought for, but its nonspecific delivery can cause a profound side effect on healthy cells. Targeted nanomedicine has the advantage of targeting cancer cells specifically by interacting with the receptors overexpressed on their surface, overcoming its non-specificity to target healthy cells. Nanocarriers prepared from biodegradable and biocompatible materials are decorated with different ligands by encapsulating therapeutic or diagnostic agents or both to target cancer cells overexpressing the receptors. Scientists are now utilizing a theranostic approach to simultaneously evaluate nanocarrier bio-distribution and its effect on the treatment regime. Herein, we have summarized the recent 5-year efforts in the development of the ligands decorated biodegradable nanocarriers, as a targeted nanomedicine approach, which has been highly promising in the treatment of cancer.
Ginsenosides Rk1 and Rg5 inhibit transforming growth factor-β1-induced epithelial-mesenchymal transition and suppress migration, invasion, anoikis resistance, and development of stem-like features in lung cancer
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Taken together, these results suggested that KMxG-GF, which is solely composed of Rg3, Rk1, and Rg5, is a stronger suppressor compared to KMxG on EMT mediated by TGF-β1. In an earlier study, we had shown that ginsenoside 20-Rg3 inhibits TGF-β1-stimulated EMT in lung cancer cells [23]. However, to the best of our knowledge, there are no studies on the effect of ginsenosides Rk1 and Rg5 on EMT.
Lung cancer has a high incidence worldwide, and most lung cancer-associated deaths are attributable to cancer metastasis. Although several medicinal properties of Panax ginseng Meyer have been reported, the effect of ginsenosides Rk1 and Rg5 on epithelial-mesenchymal transition (EMT) stimulated by transforming growth factor beta 1 (TGF- β1) and self-renewal in A549 cells is relatively unknown.
We treated TGF-β1 or alternatively Rk1 and Rg5 in A549 cells. We used western blot analysis, real-time polymerase chain reaction (qPCR), wound healing assay, Matrigel invasion assay, and anoikis assays to determine the effect of Rk1 and Rg5 on TGF-mediated EMT in lung cancer cell. In addition, we performed tumorsphere formation assays and real-time PCR to evaluate the stem-like properties.
EMT is induced by TGF-β1 in A549 cells causing the development of cancer stem-like features. Expression of E-cadherin, an epithelial marker, decreased and an increase in vimentin expression was noted. Cell mobility, invasiveness, and anoikis resistance were enhanced with TGF-β1 treatment. In addition, the expression of stem cell markers, CD44, and CD133, was also increased. Treatment with Rk1 and Rg5 suppressed EMT by TGF-β1 and the development of stemness in a dose-dependent manner. Additionally, Rk1 and Rg5 markedly suppressed TGF-β1-induced metalloproteinase-2/9 (MMP2/9) activity, and activation of Smad2/3 and nuclear factor kappa B/extra-cellular signal regulated kinases (NF-kB/ERK) pathways in lung cancer cells.
Rk1 and Rg5 regulate the EMT inducing TGF-β1 by suppressing the Smad and NF-κB/ERK pathways (non-Smad pathway).
Polysaccharide isolated from persimmon leaves (Diospyros kaki Thunb.) suppresses TGF-β1-induced epithelial-to-mesenchymal transition in A549 cells
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In various natural product studies, key factors for the mechanism of EMT regulation have been shown to be associated with the expression of Snail, Slug, and ZEB1. Delphinidin is known to inhibit EGF-induced EMT in liver cancer cell lines through the EGFR pathway and Snail inhibition, and Dioscin is known to suppress TGF-β1-induced EMT in lung cancer cell lines through the SMAD pathway as well as Snail and Slug inhibition [17]. Likewise, the decrease in Snail family levels of PLE is in the same context as the effect of inhibiting EMT, suggesting that PLE may suppress tumor metastasis, including migration and invasion.
In the present study, to verify the effect of polysaccharides derived from persimmon leaves (PLE) at epithelial-to-mesenchymal transition (EMT), A549 cells were treated with TGF-β1 alone or co-treated with TGF-β1 and PLE (50 and 75 μg/mL). PLE-treated cells showed higher expression of E-cadherin and lower expression of N-cadherin and vimentin compared to TGF-β1-treated cells by inhibiting the levels of transcription factors, including Snail, Slug, and ZEB1, all associated with EMT. PLE also significantly decreased migration, invasion, and anoikis resistance through TGF-β1 mediated EMT suppression, whereby PLE inhibited the levels of MMP-2 and MMP-9 while cleaving PARP. These inhibitory effects of PLE against EMT, migration, invasion, and anoikis resistance were determined by activating the canonical SMAD2/3 and non-canonical ERK/p38 signaling pathways. Therefore, these results suggest that PLE could be used as a potential chemical therapeutic agent for early metastasis of lung cancer in vitro.

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Dioscin suppresses TGF-β1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration and invasion

Abstract

Graphical abstract

Section snippets

Conflict of interest

Acknowledgements

Cell

Bioorg Med Chem Lett

Cancer Lett

Biochim Biophys Acta

J Chromatogr B: Anal Technol Biomed Life Sci

Toxicol Lett

Food Chem Toxicol

Toxicology

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Life Sci

Biochimie

Toxicol Appl Pharmacol

Toxicol Appl Pharmacol

Tumour invasion and metastasis initiated by microRNA-10b in breast cancer

Nature

Tumor cell interactions with the extracellular matrix during invasion and metastasis

Annu Rev Cell Biol

Cadherin switch in tumor progression

Ann N Y Acad Sci

Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis

Proc Natl Acad Sci USA

Matrix metalloproteinase-2 (MMP-2) and MMP-9 in pulmonary pathology

Exp Lung Res

Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis

Curr Pharm Biotechnol

Transgelin is a direct target of TGF-beta/Smad3-dependent epithelial cell migration in lung fibrosis

FASEB J

Protein kinase casein kinase 2-mediated upregulation of N-cadherin confers anoikis resistance on esophageal carcinoma cells

Mol Cancer Res

Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3

Mol Biol Cell

Environmental stress, erythrocyte dysfunctions, inflammation, and the metabolic syndrome: adaptations to CO2 increases?

J Cardiometab Syndr