Lysophosphatidic Acid Induces Focal Adhesion Assembly Through Rho/Rho-associated Kinase Pathway in Human Ovarian Cancer Cells

Gynecol Oncol. 2002 Dec;87(3):252-9. doi: 10.1006/gyno.2002.6831.

Abstract

Objective: The level of lysophosphatidic acid (LPA) is elevated in patients with ovarian cancer, and LPA has been reported to have a pivotal role in cancer dissemination. In the current study, the effect of LPA on the motility of ovarian cancer cells was investigated.

Methods: We analyzed the effects of LPA on the migration activity, the focal adhesion formation, and the tyrosine phosphorylation of focal adhesion proteins in human ovarian cancer cell lines Caov-3 and OVCAR-3. Inhibitors of the small GTPase Rho, one of its downstream effectors (Rho-associated kinase (ROCK)), myosin light chain kinase (MLCK), and myosin light chain (MLC) phosphatase were used to examine the mechanism of LPA-induced cellular effects.

Results: LPA enhanced the migration of ovarian cancer cells and facilitated their invasion. Rho and ROCK played essential roles in the migratory process, as evidenced by the inhibition of migration and focal adhesion formation of cancer cells by Clostridium botulinum C3 exoenzyme (C3), an inhibitor of Rho, or Y-27632, an inhibitor of ROCK. LPA also evoked the formation of focal adhesions and tyrosine phosphorylation of focal adhesion kinase and paxillin, all of which were inhibited by C3 or Y-27632.

Conclusion: These results suggest that LPA induced the migration of ovarian cancer cells, at least in part, through accelerated formation of focal adhesions mediated by Rho/ROCK-induced actomyosin contractility. This study may provide the basis for new therapies to control the metastasis of ovarian cancer.

MeSH terms

  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cytoskeletal Proteins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Female
  • Focal Adhesions / drug effects*
  • Focal Adhesions / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysophospholipids / pharmacology*
  • Myosin-Light-Chain Kinase / antagonists & inhibitors
  • Myosin-Light-Chain Kinase / metabolism
  • Myosin-Light-Chain Phosphatase
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Paxillin
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Stress Fibers / metabolism
  • Tumor Cells, Cultured
  • Tyrosine / metabolism
  • rho GTP-Binding Proteins / metabolism*
  • rho-Associated Kinases

Substances

  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Lysophospholipids
  • PXN protein, human
  • Paxillin
  • Phosphoproteins
  • Tyrosine
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Myosin-Light-Chain Kinase
  • Phosphoprotein Phosphatases
  • Myosin-Light-Chain Phosphatase
  • rho GTP-Binding Proteins