title: Nobiletin inhibits epithelial-mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-β1/Smad3 signaling pathway.
abstract: Epithelial-mesenchymal transition (EMT) is a critical cellular process in cancer metastasis, during which epithelial polarized cells become motile mesenchymal cells. Since transforming growth factor-β (TGF-β) is a potent inducer of EMT, blocking of TGF-β/Smad signaling has become a promising cancer therapy. Nobiletin, a polymethoxy flavonoid from Citrus depressa, has been shown to be valuable for cancer treatment, yet the mechanism remains unclear. In the present study, lung adenocarcinoma A549 and H1299 cells were used to evaluate the effect of nobiletin on EMT induced by TGF-β1. Nobiletin successfully inhibited TGF-β1-induced EMT, migration, invasion and adhesion in vitro, accompanied by attenuation of MMP-2, MMP-9, p-Src, p-FAK, p-paxillin, Snail, Slug, Twist and ZEB1 expression. Nobiletin inhibited the transcriptional activity of Smads without changing the phosphorylation status or translocation of Smads induced by TGF-β1. Moreover, Smad3 is requisite in TGF-β1-stimulated EMT. Smad3 overexpression meaningfully impaired the ability of nobiletin to reverse TGF-β1-induced EMT. In vivo, nobiletin prohibited the growth of metastatic nodules in the lungs of nude mice. Moreover, nobiletin inhibited tumor growth and reversed EMT in mice bearing A549-Luc xenografts, as revealed by IVIS imaging and immunohistochemical analysis. Collectively, the data suggest that nobiletin prevents EMT by inactivating TGF-β1/Smad3 signaling.
authors.affiliation: Department of Intensive Care, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Da
authors.affiliation: Department of Anesthesiology, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Chemotherapy for Lung Cancer, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Department of Radiotherapy for the Head and Neck, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Radiotherapy for the Head and Neck, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China.
authors.forename: Ruozheng
authors.initials: R
authors.lastname: Wang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D002448:Cell Adhesion; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047309:Flavones; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C008661:nobiletin