Molecular oncology, 2014-05, Vol.8 (3), p.565-580
2014
Details
- Autor(en) / Beteiligte
- Titel
- Honokiol inhibits epithelial–mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis
- Ist Teil von
- Molecular oncology, 2014-05, Vol.8 (3), p.565-580
- Ort / Verlag
- United States: Elsevier B.V
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Epithelial–mesenchymal transition (EMT), a critical step in the acquisition of metastatic state, is an attractive target for therapeutic interventions directed against tumor metastasis. Honokiol (HNK) is a natural phenolic compound isolated from an extract of seed cones from Magnolia grandiflora. Recent studies from our lab show that HNK impedes breast carcinogenesis. Here, we provide molecular evidence that HNK inhibits EMT in breast cancer cells resulting in significant downregulation of mesenchymal marker proteins and concurrent upregulation of epithelial markers. Experimental EMT induced by exposure to TGFβ and TNFα in spontaneously immortalized nontumorigenic human mammary epithelial cells is also completely reversed by HNK as evidenced by morphological as well as molecular changes. Investigating the downstream mediator(s) that may direct EMT inhibition by HNK, we found functional interactions between HNK, Stat3, and EMT-signaling components. In vitro and in vivo analyses show that HNK inhibits Stat3 activation in breast cancer cells and tumors. Constitutive activation of Stat3 abrogates HNK-mediated activation of epithelial markers whereas inhibition of Stat3 using small molecule inhibitor, Stattic, potentiates HNK-mediated inhibition of EMT markers, invasion and migration of breast cancer cells. Mechanistically, HNK inhibits recruitment of Stat3 on mesenchymal transcription factor Zeb1 promoter resulting in decreased Zeb1 expression and nuclear translocation. We also discover that HNK increases E-cadherin expression via Stat3-mediated release of Zeb1 from E-cadherin promoter. Collectively, this study reports that HNK effectively inhibits EMT in breast cancer cells and provide evidence for a previously unrecognized cross-talk between HNK and Stat3/Zeb1/E-cadherin axis. •Shows that honokiol inhibits EMT in breast cancer cells.•Reveals that Stat3 inhibition is integral for honokiol-mediated EMT inhibition.•Mechanistic insights show the involvement of Stat3/Zeb1/E-cadherin axis.•Proposes that honokiol could potentially be a rational therapeutic strategy for breast cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1574-7891eISSN: 1878-0261DOI: 10.1016/j.molonc.2014.01.004Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4009450
- Format
- –
- Schlagworte
- Antineoplastic Agents, Phytogenic - isolation & purification, Antineoplastic Agents, Phytogenic - pharmacology, Biphenyl Compounds - isolation & purification, Biphenyl Compounds - pharmacology, Breast - drug effects, Breast - metabolism, Breast cancer, Breast Neoplasms - drug therapy, Breast Neoplasms - metabolism, Cadherins - metabolism, Cancer therapies, Carcinogenesis, Cell activation, Cell Line, Tumor, Cell migration, E-cadherin, EMT, Epithelial cells, Epithelial-Mesenchymal Transition - drug effects, Female, Gene expression, Genotype & phenotype, Homeodomain Proteins - metabolism, Honokiol, Humans, Kinases, Lignans - isolation & purification, Lignans - pharmacology, Magnolia - chemistry, Magnolia grandiflora, Mammary gland, Medical research, Mesenchyme, Metastases, Metastasis, Morphology, Nuclear transport, Pharmacy, Phenolic compounds, Phosphorylation, Signal Transduction - drug effects, Stat3, Stat3 protein, STAT3 Transcription Factor - antagonists & inhibitors, STAT3 Transcription Factor - metabolism, Stem cells, Studies, Therapeutic applications, Transcription Factors - metabolism, Tumor necrosis factor-α, Tumors, Zeb1, Zinc Finger E-box-Binding Homeobox 1