title: Fasudil inhibits lysophosphatidic acid-induced invasiveness of human ovarian cancer cells.
abstract: Ovarian cancer is known to be highly invasive. The poor prognosis of advanced ovarian cancer comes from increased invasiveness of human ovarian cancer cells. The lysophosphatidic acid (LPA)/Rho/Rho-associated kinase (ROCK) pathway is intimately involved in the course of ovarian cancer progression, and the inhibition of this pathway attenuates ovarian cancer invasiveness. Fasudil (1-[5-isoquinolinesulfonyl]-homopiperazine; HA-1077) is a drug that has been in clinical use in Japan for the prevention of vasospasm after subarachnoid hemorrhage and is known to be a potent ROCK-specific inhibitor. In this study, we examined the effect of fasudil on LPA-induced invasiveness of human ovarian cancer cells to explore the potential of fasudil as an anticancer agent against ovarian cancer. Fasudil induced changes in cell morphology but not in cell viability. Fasudil significantly inhibited LPA-induced invasion and motility of human ovarian cancer cells in a dose-dependent manner. Furthermore, fasudil caused the loss of intracellular cytoskeletal rearrangement, which is necessary for cell motility, such as stress fiber formation and focal adhesion assembly. Fasudil suppressed LPA-induced tyrosine phosphorylation of paxillin, a representative focal adhesion protein, and serine phosphorylation of myosin light chain, which are essential for the process for cell migration. These findings showed that fasudil attenuated the invasiveness of human ovarian cancer cells via inhibition of the LPA/Rho/ROCK pathway. In SKOV-3ip1 ovarian cancer xenografts, intraperitoneal treatment with fasudil significantly reduced tumor burden and ascites formation. Our findings suggest that fasudil might be useful to prevent the progression of ovarian cancer in clinical settings.
authors: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Seiji
authors: S
authors: Ogata
authors: Ken-Ichirou
authors: K
authors: Morishige
authors: Kenjiro
authors: K
authors: Sawada
authors: Kae
authors: K
authors: Hashimoto
authors: Seiji
authors: S
authors: Mabuchi
authors: Chiaki
authors: C
authors: Kawase
authors: Chifumi
authors: C
authors: Ooyagi
authors: Masahiro
authors: M
authors: Sakata
authors: Tadashi
authors: T
authors: Kimura
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008246:Lysophospholipids; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C032881:lysophosphatidic acid; C049347:fasudil