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Title: PI3K Catalytic Isoform Alteration Promotes the LIMK1-related Metastasis Through the PAK1 or ROCK1/2 Activation in Cigarette Smoke-exposed Ovarian Cancer Cells. Author: Park GB, Kim D. Journal: Anticancer Res; 2017 Apr; 37(4):1805-1818. PubMed ID: 28373445. Abstract: AIM: To investigate the molecular mechanisms by which long-term exposure to cigarette smoke extract (CSE) contributes to ovarian cancer metastasis. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Characterization of the p110 isotypes of PI3K is critical for regulating cancer metastasis; LIMK1 could be a common therapeutic target of ovarian cancer metastasis.[Abstract] [Full Text] [Related] [New Search]