title: A diterpenoid compound, excisanin A, inhibits the invasive behavior of breast cancer cells by modulating the integrin β1/FAK/PI3K/AKT/β-catenin signaling.
abstract: OBJECTIVE
  Excisanin A, a diterpenoid compound purified from Isodon macrocalyxin D, has anti-cancer properties with little toxicity. In this study, the anti-invasive effects of excisanin A on breast cancer cells and its molecular mechanism of action were investigated.
  
  
  METHODS
  MTT, wound healing, transwell chamber and cell adhesion assays were utilized to investigate the effects of excisanin A on MDA-MB-231 and SKBR3 cells. Western blotting, real-time PCR, RNA interference and luciferase reporter assays were employed to determine the molecular mechanism of action of excisanin A.
  
  
  RESULTS
  Treating MDA-MB-231 and SKBR3 cells with 10-40μM excisanin A significantly inhibited cell migration and invasion and suppressed the mRNA and protein levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in a dose-dependent manner. Excisanin A efficiently abolished integrin β1 expression and reduced the phosphorylation of the downstream kinases focal adhesion kinase (FAK) and Src. Excisanin A inhibited the phosphorylation of phosphoinositide 3-kinase (PI3K), AKT and glycogen synthase kinase 3 beta (GSK3β) and down-regulated β-catenin expression and the luciferase activity of the transcription factor LEF-1. Moreover, treating breast cancer cells with siRNA targeting integrin β1 inhibited cell invasion and migration.
  
  
  CONCLUSIONS
  These results demonstrated that excisanin A inhibited invasion by suppressing MMP-2 and MMP-9 expression; the integrin β1/FAK/PI3K/AKT/β-catenin signaling pathway was involved in this process. Therefore, excisanin A might be a potential anti-metastatic chemotherapeutic agent for the treatment of breast cancer.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Qin
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Lin
authors.initials: L
authors.lastname: Jiao
authors.forename: Jiao
authors.initials: J
authors.lastname: Ji
authors.forename: Wen-Dan
authors.initials: WD
authors.lastname: Chen
authors.forename: Gong-Kan
authors.initials: GK
authors.lastname: Feng
authors.forename: You-Heng
authors.initials: YH
authors.lastname: Gao
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004224:Diterpenes; D051417:Focal Adhesion Kinase 1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; C108257:ITGB1BP1 protein, human; C047381:excisanin A; C496050:PTK2 protein, human
keywords: Diterpenoid; Excisanin A; FAK; Integrin β1; Invasion; MMPs