title: Nutlin-3 inhibits epithelial-mesenchymal transition by interfering with canonical transforming growth factor-β1-Smad-Snail/Slug axis.
abstract: Enormous efforts have been made to explore small molecules that interfere with the TGF-β signaling pathway, so as to inhibit EMT and the cancer metastasis, but few agents have been identified. In this study, we demonstrated that Nutlin-3 could abolish the down-regulation of E-cadherin induced by TGF-β1 in p53-deficient cancer cells. Further studies revealed that Nutlin-3 prohibited EMT by blocking the phosphorylation of Smad2/3, resulting in the decreased transcription of Snail/Slug. In addition, Nutlin-3 suppressed the motility of cancer cells, and potentiated the anti-proliferative activity of gefitinib and lapatinib. Collectively, Nutlin-3 could inhibit EMT and enhance the anti-cancer activity of EGFR inhibitors by interfering with the canonical TGF-β1-Smad-Snail/Slug axis, in a p53-independent manner.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yeping
authors.initials: Y
authors.lastname: Wu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Fu
authors.forename: Lin
authors.initials: L
authors.lastname: Zheng
authors.forename: Guanyu
authors.initials: G
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Jianshu
authors.initials: J
authors.lastname: Lou
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000077341:Lapatinib; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; D015820:Cadherins; D007093:Imidazoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; C508960:TGFB1 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000077341:Lapatinib; C482205:nutlin 3; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EMT; Nutlin-3; Smad pathway; TGF-β1