title: Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness.
abstract: Muscle-invasive bladder cancer is associated with a high frequency of metastasis, and fewer therapies substantially prolong survival. Silibinin, a nontoxic natural flavonoid, has been shown to exhibit pleiotropic anticancer effects in many cancer types, including bladder cancer. Our and other previous studies have demonstrated that silibinin induced apoptosis and inhibited proliferation of bladder cancer cells, whether silibinin could suppress bladder cancer metastasis has not been elucidated. In the present study, we utilized a novel highly metastatic T24-L cell model, and found that silibinin treatment not only resulted in the suppression of cell migration and invasion in vitro, but also decreased bladder cancer lung metastasis and prolonged animal survival in vivo. Mechanistically, silibinin could inhibit glycogen synthase kinase-3β (GSK3β) phosphorylation, β-catenin nuclear translocation and transactivation, and ZEB1 gene transcription that subsequently regulated the expression of cytokeratins, vimentin and matrix metalloproteinase-2 (MMP2) to reverse epithelial-mesenchymal transition (EMT). On the other hand, silibinin inhibited ZEB1 expression and then suppressed the properties of cancer stem cells (CSCs), which were evidenced as decreased spheroid colony formation, side population, and the expression of stem cell factor CD44. Overall, this study reveals a novel mechanism for silibinin targeting bladder cancer metastasis, in which inactivation of β-catenin/ZEB1 signaling by silibinin leads to dual-block of EMT and stemness.
authors.affiliation: Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Wu
authors.forename: Zhongyun
authors.initials: Z
authors.lastname: Ning
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Jinhai
authors.initials: J
authors.lastname: Fan
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhou
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.forename: Yule
authors.initials: Y
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Xinyang
authors.initials: X
authors.lastname: Wang
authors.forename: Dalin
authors.initials: D
authors.lastname: He
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020944:Silybum marianum / Q000737:chemistry; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D018398:Homeodomain Proteins; D012838:Silymarin; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin; D000077385:Silybin
keywords: Bladder cancer; CSC; EMT; Metastasis; Silibinin