The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion

K. J. Jeong, S. Y. Park, K. H. Cho, J. S. Sohn, J. Lee, Y. K. Kim, J. Kang, C. G. Park, J. W. Han, H. Y. Lee

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4279-4289
Number of pages11
JournalOncogene
Volume31
Issue number39
DOIs
StatePublished - Sep 27 2012
Externally publishedYes

Keywords

  • invasion
  • LPA
  • MMP-9
  • ovarian cancer
  • Rho/ROCK
  • uPA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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