title: PI3K Catalytic Isoform Alteration Promotes the LIMK1-related Metastasis Through the PAK1 or ROCK1/2 Activation in Cigarette Smoke-exposed Ovarian Cancer Cells.
abstract: To investigate the molecular mechanisms by which long-term exposure to cigarette smoke extract (CSE) contributes to ovarian cancer metastasis.
  
  
  
  Western blot analysis for diverse p110 isoforms of phosphoinositide 3-kinase (PI3K)-related signaling pathway and epithelial-mesenchymal transition (EMT) markers was performed to analyze the underlying mechanisms. Migratory activity of CSE-exposed ovarian cancer cells was determined by transendothelial migration and invasion assay.
  
  
  
  After exposure to CSE for four weeks, CaOV3 (primary) and SKOV3 (metastatic) ovarian cancer cells showed enhanced mesenchymal characteristics and produced EMT-related cytokines [intwerleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGF-β1)]. CSE exposure activated the Src-p110δ-p21 protein-activated kinase 1 (PAK1) in CaOV3 cells and the Lyn-p110β-Rho-associated kinases 1/2 (ROCK1/2) in SKOV3 cells, which led to the stimulation of LIM kinase 1 (LIMK1) phosphorylation and TGF-β1 release. LIMK1 knockdown efficiently blocked the migratory activity and suppressed the mesenchymal phenotypes of CSE-treated ovarian cancer cells. Reactive oxygen species (ROS) initiated the CSE-mediated EMT processes in ovarian cancer cells.
  
  
  
  Characterization of the p110 isotypes of PI3K is critical for regulating cancer metastasis; LIMK1 could be a common therapeutic target of ovarian cancer metastasis.
authors.affiliation: Department of Biochemistry, Kosin University College of Medicine, Busan, Republic of Korea.
authors.forename: Ga Bin
authors.initials: GB
authors.lastname: Park
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea kimdj@inje.ac.kr.
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D054462:p21-Activated Kinases / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D019869:Phosphatidylinositol 3-Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515903:PAK1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C515851:ROCK1 protein, human; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases
keywords: LIM kinase 1; Phosphoinositide 3-kinase; cigarette smoke extract; epithelial-mesenchymal transition; ovarian cancer; p21 protein-activated kinase 1; rho-associated kinases 1/2