title: The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion.
abstract: Lysophosphatidic acid (LPA) is a biolipid that has diverse biological activities implicated in ovarian cancer initiation and progression. Previous studies have shown the critical role of the Rho/Rho-associated kinase (ROCK) pathway in LPA-induced ovarian cancer progression. However, detailed underlying mechanism by which the Rho/ROCK pathway induces ovarian cancer cell invasion is still incompletely understood. In the present study, we observed that the Rho/ROCK pathway is implicated in the production of proteolytic enzymes, leading to LPA-induced ovarian cancer cell invasion. LPA induced matrix metalloproteinase (MMP)-9 expression in CAOV-3 and PA-1 cells and urokinase-type plasminogen activator (uPA) expression in SKOV-3 cells. LPA-induced proteolytic enzyme expression was required for the invasion of ovarian cancer cells expressing corresponding enzymes. Pretreatment of cells with a pharmacological inhibitor of Rho/ROCK (Y-27632) or overexpression of a dominant-negative mutant of Rho (Rho N19) profoundly inhibited LPA-induced proteolytic enzyme expression as well as the invasive potential of ovarian cancer cells. In addition, transfection with dominant-negative Ras (Ras N17) significantly inhibited LPA-induced Rho activation as well as MMP-9 and uPA expression. Consistently, Y-27632 reduced LPA-induced nuclear factor (NF)-κB activation that is critical for proteolytic enzyme expression and cellular invasion. Collectively, we demonstrate a mechanism by which LPA promotes ovarian cancer progression through coordinate activation of a Ras/Rho/ROCK/NF-κB signaling pathway and the proteolytic enzyme secretion, providing novel biomarkers and promising therapeutic targets for ovarian cancer cell progression.
authors.affiliation: Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: K J
authors.initials: KJ
authors.lastname: Jeong
authors.forename: S Y
authors.initials: SY
authors.lastname: Park
authors.forename: K H
authors.initials: KH
authors.lastname: Cho
authors.forename: J S
authors.initials: JS
authors.lastname: Sohn
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: Y K
authors.initials: YK
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Kang
authors.forename: C G
authors.initials: CG
authors.lastname: Park
authors.forename: J W
authors.initials: JW
authors.lastname: Han
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000577:Amides / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009570:Nitriles / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D010447:Peptide Hydrolases / Q000096:biosynthesis*; D011725:Pyridines / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000577:Amides; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D016328:NF-kappa B; D009570:Nitriles; D011725:Pyridines; D013450:Sulfones; C108830:Y 27632; D054460:rho-Associated Kinases; D010447:Peptide Hydrolases; D014568:Urokinase-Type Plasminogen Activator; C032881:lysophosphatidic acid