Lysophosphatidic acid enhances epithelial ovarian carcinoma invasion through the increased expression of interleukin-8

Gynecol Oncol. 2004 Nov;95(2):314-22. doi: 10.1016/j.ygyno.2004.08.001.


Objective: We previously reported that lysophosphatidic acid (LPA) stimulates cellular invasion of ovarian cancer (OVCA) cells by enhancing membrane-type-1-matrix metalloproteinase (MT1-MMP)-mediated activation of MMP2. Here, we investigate a second mechanism in which LPA enhances cellular invasion through the increased expression of IL-8, independent of the expression or activation of MMP2.

Methods: Epithelial ovarian carcinoma cells (DOV 13) were exposed to LPA (80 microM) and IL-8 (100 ng/ml) for 24 h. IL-8 expression was quantified by enzyme-linked immunosorbent assay (ELISA). Cellular invasion (Matrigel invasion), migration (colloidal gold), and urinary-type plasminogen activator (uPA) activity (colorimetric assay) were quantified. Conditioned medium was also assayed for MMP activation and expression by SDS-PAGE gelatin zymography, ELISA, and Western blotting. In addition, IL-8 neutralizing antibody and MMP inhibitors were employed.

Results: Our results found LPA to increase IL-8 expression threefold. IL-8 did not affect cellular migration, MMP2 activation, or uPA expression. However, exposure to various concentrations of IL-8 increased cellular invasiveness. Using an IL-8 blocking antibody and various MMP inhibitors, we determined that the increase in invasion was IL-8-dependent, while independent of the activation of MMP2 or MMP9. We further determined IL-8 exposure increased the expression of matrilysin (MMP7). Cells exposed to LPA and IL-8 resulted in a synergistic effect on cellular invasion. Adding the IL-8 blocking antibody, slightly decreased cellular invasion, indicating LPA in part, increases cellular invasion through the increased expression of IL-8.

Conclusion: We have identified a separate mechanism of enhanced cellular invasion, which is independent of MMP2 activation and involves the increased expression of IL-8 and subsequent increased expression of MMP7.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Enzyme Activation / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Interleukin-8 / biosynthesis*
  • Lysophospholipids / pharmacology*
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 7 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Neoplasm Invasiveness
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / pathology*


  • Interleukin-8
  • Lysophospholipids
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 7
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 1
  • lysophosphatidic acid